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Muoio, Deborah Marie

Overview:

Dr. Deborah Muoio is an Associate Professor in the Sarah. W. Stedman Nutrition and Metabolism Center, with appointments in the Departments of Medicine and Pharmacology & Cancer Biology. Her laboratory investigates mechanisms of metabolic regulation in skeletal muscle, with emphasis on molecular events that link overnutrition and inactivity to the development of insulin resistance. Her program features a multidisciplinary approach that combines integrative physiology and intermediary metabolism with cellular and molecular biochemistry, using model systems that range from primary human myocytes to genetically engineered mice. Recent studies by her research team have employed mass spectrometry-based metabolomics as a tool to understand the interplay between mitochondrial energetics and insulin action. Emergent findings from this work suggest that obesity-associated glucose intolerance stems from excessive β-oxidation and lipid-induced mitochondrial stress. Ongoing studies seek to identify signaling mechanisms that mediate crosstalk between muscle mitochondria and glucose regulatory pathways, with the goal of realizing new therapeutic opportunities for treating metabolic diseases. Three main project areas of her laboratory include: 1) mechanisms that link lipid oversupply to mitochondrial malfunction and insulin resistance in skeletal muscle, 2) mechanisms through which exercise enhances mitochondrial function, lipid tolerance and insulin sensitivity, and 3) translational studies to examine the impact of diet and/or exercise interventions on metabolic regulation and mitochondrial function in human skeletal muscle. This research is supported by grants from the NIH and the American Diabetes Association.

Positions:

Professor of Medicine

Medicine, Endocrinology, Metabolism, and Nutrition
School of Medicine

Professor in Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member of Sarah W. Stedman Nutrition and Metabolism Center

Sarah Stedman Nutrition & Metabolism Center
School of Medicine

Education:

Ph.D. 1999

Ph.D. — University of North Carolina at Chapel Hill

News:

Grants:

STIM1 and metabolic flexibility

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 2017
End Date
March 31, 2022

Interdisciplinary Research Training Program in AIDS

Administered By
Medicine, Infectious Diseases
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 2010
End Date
August 31, 2020

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
June 30, 2020

Microbial regulation of host nutrient metabolism

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
May 01, 2013
End Date
May 31, 2020

Role of Carnitine Acetyltransferase in Mitochondrial and Metabolic Function

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2010
End Date
March 31, 2019

Role of Protein Malonylation in Regulating Mitochondrial Function

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2015
End Date
September 29, 2018

Mitochondrial Protein Acetylation and Energy Metabolism in Muscle

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 29, 2015
End Date
April 28, 2018

Carnitine Acetyltransferase and Metabolic Regulation in the Exocrine Pancreas

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2015
End Date
September 29, 2017

Systems Biology Approaches for Predicting Cardiometabolic Risk in Persons Living with HIV

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 03, 2015
End Date
August 31, 2017

Organic Cations and Mitochondrial Efficiency

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
East Carolina University
Role
Principal Investigator
Start Date
July 01, 2016
End Date
June 30, 2017

Medical Scientist Training Program

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1997
End Date
June 30, 2017

Duke Training Grant in Nephrology

Administered By
Medicine, Nephrology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
September 20, 1995
End Date
June 30, 2017

Regulation of Islet Beta-Cell Function via Islet-Derived VGF Peptides

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
September 04, 2013
End Date
June 30, 2016

Iron homeostasis in mammalian muscle

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
July 01, 2011
End Date
March 31, 2016

Metabolic Regulators of Insulin Secretion and Insulin Resistance

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
September 30, 2013
End Date
August 31, 2015

Mechanisms of Insulin Resistance in Rheumatoid Arthritis

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
September 05, 2008
End Date
August 31, 2015

Behavior And Physiology In Aging

Administered By
Center for the Study of Aging and Human Development
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1999
End Date
August 31, 2015

Instrumentation for Quantitative Phosphoproteomics and Acetylomics

Administered By
Duke Center for Genomic and Computational Biology
AwardedBy
National Institutes of Health
Role
Major User
Start Date
May 15, 2014
End Date
May 14, 2015

Exercise Dose-Response Effects in Prediabetes:Responses and Mechanisms

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
June 29, 2009
End Date
March 31, 2015

Fat Oxidation, Redox Stress and Insulin Resistance in Skeletal Muscle

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2011
End Date
August 31, 2014

Role of Carnitine Acetyltansferase in Combatting Nutrient Stress

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2011
End Date
July 31, 2014

Mechanisms of Insulin Resistance in Rheumatoid Arthritis

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
September 05, 2008
End Date
August 31, 2013

Mechanisms linking the adipogenic phenotype of aging muscle to insulin resistance

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 15, 2006
End Date
August 31, 2012

Macrophage Mitochondrial Stress in Inflammation, Insulin Resistance & Obesity

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
August 01, 2007
End Date
January 31, 2010

Regulation and metabolic impact of mitochondrial CD36 in skeletal muscle

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
December 01, 2006
End Date
November 30, 2009

Role of carnitine acetyltransferase in mitochondrial function and insulin action

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 14, 2007
End Date
September 13, 2009

Molecular Genetics of Muscle Specialization

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 01, 2001
End Date
June 30, 2009

Ketone Dysregulation and Muscle Insulin Resistance

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2004
End Date
June 30, 2007
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Publications:

SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion.

Sirtuins are NAD+-dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control have remained enigmatic. Using a combination of phylogenetics, structural biology, and enzymology, we show that SIRT4 removes three acyl moieties from lysine residues: methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine. The metabolites leading to these post-translational modifications are intermediates in leucine oxidation, and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metabolism in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance. These findings identify a robust enzymatic activity for SIRT4, uncover a mechanism controlling branched-chain amino acid flux, and position SIRT4 as a crucial player maintaining insulin secretion and glucose homeostasis during aging.

Authors
Anderson, KA; Huynh, FK; Fisher-Wellman, K; Stuart, JD; Peterson, BS; Douros, JD; Wagner, GR; Thompson, JW; Madsen, AS; Green, MF; Sivley, RM; Ilkayeva, OR; Stevens, RD; Backos, DS; Capra, JA; Olsen, CA; Campbell, JE; Muoio, DM; Grimsrud, PA; Hirschey, MD
MLA Citation
Anderson, KA, Huynh, FK, Fisher-Wellman, K, Stuart, JD, Peterson, BS, Douros, JD, Wagner, GR, Thompson, JW, Madsen, AS, Green, MF, Sivley, RM, Ilkayeva, OR, Stevens, RD, Backos, DS, Capra, JA, Olsen, CA, Campbell, JE, Muoio, DM, Grimsrud, PA, and Hirschey, MD. "SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion." Cell metabolism 25.4 (April 2017): 838-855.e15.
PMID
28380376
Source
epmc
Published In
Cell Metabolism
Volume
25
Issue
4
Publish Date
2017
Start Page
838
End Page
855.e15
DOI
10.1016/j.cmet.2017.03.003

HDAC3 sets the timer on muscle fuel switching.

Authors
Muoio, DM
MLA Citation
Muoio, DM. "HDAC3 sets the timer on muscle fuel switching." Nature medicine 23.2 (February 2017): 148-150.
PMID
28170378
Source
epmc
Published In
Nature Medicine
Volume
23
Issue
2
Publish Date
2017
Start Page
148
End Page
150
DOI
10.1038/nm.4282

Molecular alterations in skeletal muscle in rheumatoid arthritis are related to disease activity, physical inactivity, and disability.

To identify molecular alterations in skeletal muscle in rheumatoid arthritis (RA) that may contribute to ongoing disability in RA.Persons with seropositive or erosive RA (n = 51) and control subjects matched for age, gender, race, body mass index (BMI), and physical activity (n = 51) underwent assessment of disease activity, disability, pain, physical activity and thigh muscle biopsies. Muscle tissue was used for measurement of pro-inflammatory markers, transcriptomics, and comprehensive profiling of metabolic intermediates. Groups were compared using mixed models. Bivariate associations were assessed with Spearman correlation.Compared to controls, patients with RA had 75% greater muscle concentrations of IL-6 protein (p = 0.006). In patients with RA, muscle concentrations of inflammatory markers were positively associated (p < 0.05 for all) with disease activity (IL-1β, IL-8), disability (IL-1β, IL-6), pain (IL-1β, TNF-α, toll-like receptor (TLR)-4), and physical inactivity (IL-1β, IL-6). Muscle cytokines were not related to corresponding systemic cytokines. Prominent among the gene sets differentially expressed in muscles in RA versus controls were those involved in skeletal muscle repair processes and glycolytic metabolism. Metabolic profiling revealed 46% higher concentrations of pyruvate in muscle in RA (p < 0.05), and strong positive correlation between levels of amino acids involved in fibrosis (arginine, ornithine, proline, and glycine) and disability (p < 0.05).RA is accompanied by broad-ranging molecular alterations in skeletal muscle. Analysis of inflammatory markers, gene expression, and metabolic intermediates linked disease-related disruptions in muscle inflammatory signaling, remodeling, and metabolic programming to physical inactivity and disability. Thus, skeletal muscle dysfunction might contribute to a viscous cycle of RA disease activity, physical inactivity, and disability.

Authors
Huffman, KM; Jessee, R; Andonian, B; Davis, BN; Narowski, R; Huebner, JL; Kraus, VB; McCracken, J; Gilmore, BF; Tune, KN; Campbell, M; Koves, TR; Muoio, DM; Hubal, MJ; Kraus, WE
MLA Citation
Huffman, KM, Jessee, R, Andonian, B, Davis, BN, Narowski, R, Huebner, JL, Kraus, VB, McCracken, J, Gilmore, BF, Tune, KN, Campbell, M, Koves, TR, Muoio, DM, Hubal, MJ, and Kraus, WE. "Molecular alterations in skeletal muscle in rheumatoid arthritis are related to disease activity, physical inactivity, and disability." Arthritis research & therapy 19.1 (January 23, 2017): 12-.
Website
http://hdl.handle.net/10161/13703
PMID
28114971
Source
epmc
Published In
Arthritis Research and Therapy
Volume
19
Issue
1
Publish Date
2017
Start Page
12
DOI
10.1186/s13075-016-1215-7

Comprehensive metabolic modeling of multiple 13C-isotopomer data sets to study metabolism in perfused working hearts.

In many forms of cardiomyopathy, alterations in energy substrate metabolism play a key role in disease pathogenesis. Stable isotope tracing in rodent heart perfusion systems can be used to determine cardiac metabolic fluxes, namely those relative fluxes that contribute to pyruvate, the acetyl-CoA pool, and pyruvate anaplerosis, which are critical to cardiac homeostasis. Methods have previously been developed to interrogate these relative fluxes using isotopomer enrichments of measured metabolites and algebraic equations to determine a predefined metabolic flux model. However, this approach is exquisitely sensitive to measurement error, thus precluding accurate relative flux parameter determination. In this study, we applied a novel mathematical approach to determine relative cardiac metabolic fluxes using 13C-metabolic flux analysis (13C-MFA) aided by multiple tracer experiments and integrated data analysis. Using 13C-MFA, we validated a metabolic network model to explain myocardial energy substrate metabolism. Four different 13C-labeled substrates were queried (i.e., glucose, lactate, pyruvate, and oleate) based on a previously published study. We integrated the analysis of the complete set of isotopomer data gathered from these mouse heart perfusion experiments into a single comprehensive network model that delineates substrate contributions to both pyruvate and acetyl-CoA pools at a greater resolution than that offered by traditional methods using algebraic equations. To our knowledge, this is the first rigorous application of 13C-MFA to interrogate data from multiple tracer experiments in the perfused heart. We anticipate that this approach can be used widely to study energy substrate metabolism in this and other similar biological systems.

Authors
Crown, SB; Kelleher, JK; Rouf, R; Muoio, DM; Antoniewicz, MR
MLA Citation
Crown, SB, Kelleher, JK, Rouf, R, Muoio, DM, and Antoniewicz, MR. "Comprehensive metabolic modeling of multiple 13C-isotopomer data sets to study metabolism in perfused working hearts." American journal of physiology. Heart and circulatory physiology 311.4 (October 2016): H881-H891.
PMID
27496880
Source
epmc
Published In
American journal of physiology. Heart and circulatory physiology
Volume
311
Issue
4
Publish Date
2016
Start Page
H881
End Page
H891
DOI
10.1152/ajpheart.00428.2016

Plasma acylcarnitines during insulin stimulation in humans are reflective of age-related metabolic dysfunction.

The purpose of this study was to determine if plasma acylcarnitine (AC) profiling is altered under hyperinsulinemic conditions as part of the aging process. Fifteen young, lean (19-29 years) and fifteen middle-to older-aged (57-82 years) individuals underwent a 2-hr euglycemic-hyperinsulinemic clamp. Plasma samples were obtained at baseline, 20 min, 50 min, and 120 min for analysis of AC species and amino acids. Skeletal muscle biopsies were performed after 60 min of insulin-stimulation for analysis of acetyl-CoA carboxylase (ACC) phosphorylation. Insulin infusion decreased the majority of plasma short-, medium-, and long-chain (SC, MC, and LC, respectively) AC. However, during the initial 50 min, a number of MC and LC AC species (C10, C10:1, C12:1, C14, C16, C16:1, C18) remained elevated in aged individuals compared to their younger counterparts indicating a lag in responsiveness. Additionally, the insulin-induced decline in skeletal muscle ACC phosphorylation was blunted in the aged compared to young individuals (-24% vs. -56%, P < 0.05). These data suggest that a desensitization to insulin during aging, possibly at the level of skeletal muscle ACC phosphorylation, results in a diminished ability to transition to glucose oxidation indicative of metabolic inflexibility.

Authors
Consitt, LA; Koves, TR; Muoio, DM; Nakazawa, M; Newton, CA; Houmard, JA
MLA Citation
Consitt, LA, Koves, TR, Muoio, DM, Nakazawa, M, Newton, CA, and Houmard, JA. "Plasma acylcarnitines during insulin stimulation in humans are reflective of age-related metabolic dysfunction." Biochemical and biophysical research communications 479.4 (October 2016): 868-874.
PMID
27693789
Source
epmc
Published In
Biochemical and Biophysical Research Communications
Volume
479
Issue
4
Publish Date
2016
Start Page
868
End Page
874
DOI
10.1016/j.bbrc.2016.09.116

Mitochondrial protein hyperacetylation in the failing heart.

Myocardial fuel and energy metabolic derangements contribute to the pathogenesis of heart failure. Recent evidence implicates posttranslational mechanisms in the energy metabolic disturbances that contribute to the pathogenesis of heart failure. We hypothesized that accumulation of metabolite intermediates of fuel oxidation pathways drives posttranslational modifications of mitochondrial proteins during the development of heart failure. Myocardial acetylproteomics demonstrated extensive mitochondrial protein lysine hyperacetylation in the early stages of heart failure in well-defined mouse models and the in end-stage failing human heart. To determine the functional impact of increased mitochondrial protein acetylation, we focused on succinate dehydrogenase A (SDHA), a critical component of both the tricarboxylic acid (TCA) cycle and respiratory complex II. An acetyl-mimetic mutation targeting an SDHA lysine residue shown to be hyperacetylated in the failing human heart reduced catalytic function and reduced complex II-driven respiration. These results identify alterations in mitochondrial acetyl-CoA homeostasis as a potential driver of the development of energy metabolic derangements that contribute to heart failure.

Authors
Horton, JL; Martin, OJ; Lai, L; Riley, NM; Richards, AL; Vega, RB; Leone, TC; Pagliarini, DJ; Muoio, DM; Bedi, KC; Margulies, KB; Coon, JJ; Kelly, DP
MLA Citation
Horton, JL, Martin, OJ, Lai, L, Riley, NM, Richards, AL, Vega, RB, Leone, TC, Pagliarini, DJ, Muoio, DM, Bedi, KC, Margulies, KB, Coon, JJ, and Kelly, DP. "Mitochondrial protein hyperacetylation in the failing heart." JCI insight 2.1 (February 25, 2016).
PMID
26998524
Source
epmc
Published In
JCI insight
Volume
2
Issue
1
Publish Date
2016

The Failing Heart Relies on Ketone Bodies as a Fuel.

Significant evidence indicates that the failing heart is energy starved. During the development of heart failure, the capacity of the heart to utilize fatty acids, the chief fuel, is diminished. Identification of alternate pathways for myocardial fuel oxidation could unveil novel strategies to treat heart failure.Quantitative mitochondrial proteomics was used to identify energy metabolic derangements that occur during the development of cardiac hypertrophy and heart failure in well-defined mouse models. As expected, the amounts of proteins involved in fatty acid utilization were downregulated in myocardial samples from the failing heart. Conversely, expression of β-hydroxybutyrate dehydrogenase 1, a key enzyme in the ketone oxidation pathway, was increased in the heart failure samples. Studies of relative oxidation in an isolated heart preparation using ex vivo nuclear magnetic resonance combined with targeted quantitative myocardial metabolomic profiling using mass spectrometry revealed that the hypertrophied and failing heart shifts to oxidizing ketone bodies as a fuel source in the context of reduced capacity to oxidize fatty acids. Distinct myocardial metabolomic signatures of ketone oxidation were identified.These results indicate that the hypertrophied and failing heart shifts to ketone bodies as a significant fuel source for oxidative ATP production. Specific metabolite biosignatures of in vivo cardiac ketone utilization were identified. Future studies aimed at determining whether this fuel shift is adaptive or maladaptive could unveil new therapeutic strategies for heart failure.

Authors
Aubert, G; Martin, OJ; Horton, JL; Lai, L; Vega, RB; Leone, TC; Koves, T; Gardell, SJ; Krüger, M; Hoppel, CL; Lewandowski, ED; Crawford, PA; Muoio, DM; Kelly, DP
MLA Citation
Aubert, G, Martin, OJ, Horton, JL, Lai, L, Vega, RB, Leone, TC, Koves, T, Gardell, SJ, Krüger, M, Hoppel, CL, Lewandowski, ED, Crawford, PA, Muoio, DM, and Kelly, DP. "The Failing Heart Relies on Ketone Bodies as a Fuel." Circulation 133.8 (February 2016): 698-705.
PMID
26819376
Source
epmc
Published In
Circulation
Volume
133
Issue
8
Publish Date
2016
Start Page
698
End Page
705
DOI
10.1161/circulationaha.115.017355

The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins.

Lysine acetylation (AcK), a posttranslational modification wherein a two-carbon acetyl group binds covalently to a lysine residue, occurs prominently on mitochondrial proteins and has been linked to metabolic dysfunction. An emergent theory suggests mitochondrial AcK occurs via mass action rather than targeted catalysis. To test this hypothesis, we performed mass spectrometry-based acetylproteomic analyses of quadriceps muscles from mice with skeletal muscle-specific deficiency of carnitine acetyltransferase (CrAT), an enzyme that buffers the mitochondrial acetyl-CoA pool by converting short-chain acyl-CoAs to their membrane permeant acylcarnitine counterparts. CrAT deficiency increased tissue acetyl-CoA levels and susceptibility to diet-induced AcK of broad-ranging mitochondrial proteins, coincident with diminished whole body glucose control. Sub-compartment acetylproteome analyses of muscles from obese mice and humans showed remarkable overrepresentation of mitochondrial matrix proteins. These findings reveal roles for CrAT and L-carnitine in modulating the muscle acetylproteome and provide strong experimental evidence favoring the nonenzymatic carbon pressure model of mitochondrial AcK.

Authors
Davies, MN; Kjalarsdottir, L; Thompson, JW; Dubois, LG; Stevens, RD; Ilkayeva, OR; Brosnan, MJ; Rolph, TP; Grimsrud, PA; Muoio, DM
MLA Citation
Davies, MN, Kjalarsdottir, L, Thompson, JW, Dubois, LG, Stevens, RD, Ilkayeva, OR, Brosnan, MJ, Rolph, TP, Grimsrud, PA, and Muoio, DM. "The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins." Cell reports 14.2 (January 2016): 243-254.
PMID
26748706
Source
epmc
Published In
Cell Reports
Volume
14
Issue
2
Publish Date
2016
Start Page
243
End Page
254
DOI
10.1016/j.celrep.2015.12.030

Diabetes: The good in fat

Authors
Muoio, DM; Newgard, CB
MLA Citation
Muoio, DM, and Newgard, CB. "Diabetes: The good in fat." Nature 516.7529 (December 4, 2015): 49-50.
Source
scopus
Published In
Nature
Volume
516
Issue
7529
Publish Date
2015
Start Page
49
End Page
50
DOI
10.1038/nature14070

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.

Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6-2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk.

Authors
Kraus, WE; Muoio, DM; Stevens, R; Craig, D; Bain, JR; Grass, E; Haynes, C; Kwee, L; Qin, X; Slentz, DH; Krupp, D; Muehlbauer, M; Hauser, ER; Gregory, SG; Newgard, CB; Shah, SH
MLA Citation
Kraus, WE, Muoio, DM, Stevens, R, Craig, D, Bain, JR, Grass, E, Haynes, C, Kwee, L, Qin, X, Slentz, DH, Krupp, D, Muehlbauer, M, Hauser, ER, Gregory, SG, Newgard, CB, and Shah, SH. "Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis." PLoS genetics 11.11 (November 5, 2015): e1005553-.
Website
http://hdl.handle.net/10161/10957
PMID
26540294
Source
epmc
Published In
PLoS genetics
Volume
11
Issue
11
Publish Date
2015
Start Page
e1005553
DOI
10.1371/journal.pgen.1005553

Metabolic Catastrophe in Mice Lacking Transferrin Receptor in Muscle.

Transferrin receptor (Tfr1) is ubiquitously expressed, but its roles in non-hematopoietic cells are incompletely understood. We used a tissue-specific conditional knockout strategy to ask whether skeletal muscle required Tfr1 for iron uptake. We found that iron assimilation via Tfr1 was critical for skeletal muscle metabolism, and that iron deficiency in muscle led to dramatic changes, not only in muscle, but also in adipose tissue and liver. Inactivation of Tfr1 incapacitated normal energy production in muscle, leading to growth arrest and a muted attempt to switch to fatty acid β oxidation, using up fat stores. Starvation signals stimulated gluconeogenesis in the liver, but amino acid substrates became limiting and hypoglycemia ensued. Surprisingly, the liver was also iron deficient, and production of the iron regulatory hormone hepcidin was depressed. Our observations reveal a complex interaction between iron homeostasis and metabolism that has implications for metabolic and iron disorders.

Authors
Barrientos, T; Laothamatas, I; Koves, TR; Soderblom, EJ; Bryan, M; Moseley, MA; Muoio, DM; Andrews, NC
MLA Citation
Barrientos, T, Laothamatas, I, Koves, TR, Soderblom, EJ, Bryan, M, Moseley, MA, Muoio, DM, and Andrews, NC. "Metabolic Catastrophe in Mice Lacking Transferrin Receptor in Muscle." EBioMedicine 2.11 (November 2015): 1705-1717.
PMID
26870796
Source
epmc
Published In
EBioMedicine
Volume
2
Issue
11
Publish Date
2015
Start Page
1705
End Page
1717
DOI
10.1016/j.ebiom.2015.09.041

ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate.

In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, the loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased under hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4, likely via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that the ACC1/ACLY-α-ketoglutarate-ETV4 axis is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future.

Authors
Keenan, MM; Liu, B; Tang, X; Wu, J; Cyr, D; Stevens, RD; Ilkayeva, O; Huang, Z; Tollini, LA; Murphy, SK; Lucas, J; Muoio, DM; Kim, SY; Chi, J-T
MLA Citation
Keenan, MM, Liu, B, Tang, X, Wu, J, Cyr, D, Stevens, RD, Ilkayeva, O, Huang, Z, Tollini, LA, Murphy, SK, Lucas, J, Muoio, DM, Kim, SY, and Chi, J-T. "ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate." PLoS genetics 11.10 (October 9, 2015): e1005599-.
Website
http://hdl.handle.net/10161/13614
PMID
26452058
Source
epmc
Published In
PLoS genetics
Volume
11
Issue
10
Publish Date
2015
Start Page
e1005599
DOI
10.1371/journal.pgen.1005599

Increased palmitate intake: higher acylcarnitine concentrations without impaired progression of β-oxidation.

Palmitic acid (PA) is associated with higher blood concentrations of medium-chain acylcarnitines (MCACs), and we hypothesized that PA may inhibit progression of FA β-oxidation. Using a cross-over design, 17 adults were fed high PA (HPA) and low PA/high oleic acid (HOA) diets, each for 3 weeks. The [1-(13)C]PA and [13-(13)C]PA tracers were administered with food in random order with each diet, and we assessed PA oxidation (PA OX) and serum AC concentration to determine whether a higher PA intake promoted incomplete PA OX. Dietary PA was completely oxidized during the HOA diet, but only about 40% was oxidized during the HPA diet. The [13-(13)C]PA/[1-(13)C]PA ratio of PA OX had an approximate value of 1.0 for either diet, but the ratio of the serum concentrations of MCACs to long-chain ACs (LCACs) was significantly higher during the HPA diet. Thus, direct measurement of PA OX did not confirm that the HPA diet caused incomplete PA OX, despite the modest, but statistically significant, increase in the ratio of MCACs to LCACs in blood.

Authors
Kien, CL; Matthews, DE; Poynter, ME; Bunn, JY; Fukagawa, NK; Crain, KI; Ebenstein, DB; Tarleton, EK; Stevens, RD; Koves, TR; Muoio, DM
MLA Citation
Kien, CL, Matthews, DE, Poynter, ME, Bunn, JY, Fukagawa, NK, Crain, KI, Ebenstein, DB, Tarleton, EK, Stevens, RD, Koves, TR, and Muoio, DM. "Increased palmitate intake: higher acylcarnitine concentrations without impaired progression of β-oxidation." Journal of lipid research 56.9 (September 2015): 1795-1807.
PMID
26156077
Source
epmc
Published In
Journal of lipid research
Volume
56
Issue
9
Publish Date
2015
Start Page
1795
End Page
1807
DOI
10.1194/jlr.m060137

SIRT3 Directs Carbon Traffic in Muscle to Promote Glucose Control.

Authors
Huynh, FK; Muoio, DM; Hirschey, MD
MLA Citation
Huynh, FK, Muoio, DM, and Hirschey, MD. "SIRT3 Directs Carbon Traffic in Muscle to Promote Glucose Control." Diabetes 64.9 (September 2015): 3058-3060.
PMID
26294425
Source
epmc
Published In
Diabetes
Volume
64
Issue
9
Publish Date
2015
Start Page
3058
End Page
3060
DOI
10.2337/db15-0709

Abstract 3004: Contextual RNAi screen identifies ACLY and ACC1 as mediators of hypoxia-induced apoptosis through metabolic and transcriptional mechanisms

Authors
Keenan, MM; Liu, B; Tang, X; Wu, J; Cyr, D; Stevens, RD; Ilkayeva, O; Lucas, J; Muoio, DM; Kim, SY; Chi, J-T
MLA Citation
Keenan, MM, Liu, B, Tang, X, Wu, J, Cyr, D, Stevens, RD, Ilkayeva, O, Lucas, J, Muoio, DM, Kim, SY, and Chi, J-T. "Abstract 3004: Contextual RNAi screen identifies ACLY and ACC1 as mediators of hypoxia-induced apoptosis through metabolic and transcriptional mechanisms." August 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
15 Supplement
Publish Date
2015
Start Page
3004
End Page
3004
DOI
10.1158/1538-7445.AM2015-3004

Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits.

The beneficial effects of physical activity (PA) are well documented, yet the mechanisms by which PA prevents disease and improves health outcomes are poorly understood. To identify major gaps in knowledge and potential strategies for catalyzing progress in the field, the NIH convened a workshop in late October 2014 entitled "Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits." Presentations and discussions emphasized the challenges imposed by the integrative and intermittent nature of PA, the tremendous discovery potential of applying "-omics" technologies to understand interorgan crosstalk and biological networking systems during PA, and the need to establish an infrastructure of clinical trial sites with sufficient expertise to incorporate mechanistic outcome measures into adequately sized human PA trials. Identification of the mechanisms that underlie the link between PA and improved health holds extraordinary promise for discovery of novel therapeutic targets and development of personalized exercise medicine.

Authors
Neufer, PD; Bamman, MM; Muoio, DM; Bouchard, C; Cooper, DM; Goodpaster, BH; Booth, FW; Kohrt, WM; Gerszten, RE; Mattson, MP; Hepple, RT; Kraus, WE; Reid, MB; Bodine, SC; Jakicic, JM; Fleg, JL; Williams, JP; Joseph, L; Evans, M; Maruvada, P; Rodgers, M; Roary, M; Boyce, AT; Drugan, JK; Koenig, JI; Ingraham, RH; Krotoski, D; Garcia-Cazarin, M; McGowan, JA; Laughlin, MR
MLA Citation
Neufer, PD, Bamman, MM, Muoio, DM, Bouchard, C, Cooper, DM, Goodpaster, BH, Booth, FW, Kohrt, WM, Gerszten, RE, Mattson, MP, Hepple, RT, Kraus, WE, Reid, MB, Bodine, SC, Jakicic, JM, Fleg, JL, Williams, JP, Joseph, L, Evans, M, Maruvada, P, Rodgers, M, Roary, M, Boyce, AT, Drugan, JK, Koenig, JI, Ingraham, RH, Krotoski, D, Garcia-Cazarin, M, McGowan, JA, and Laughlin, MR. "Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits." Cell metabolism 22.1 (July 2015): 4-11.
PMID
26073496
Source
epmc
Published In
Cell Metabolism
Volume
22
Issue
1
Publish Date
2015
Start Page
4
End Page
11
DOI
10.1016/j.cmet.2015.05.011

Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise.

Acylcarnitine metabolites have gained attention as biomarkers of nutrient stress, but their physiological relevance and metabolic purpose remain poorly understood. Short-chain carnitine conjugates, including acetylcarnitine, derive from their corresponding acyl-CoA precursors via the action of carnitine acetyltransferase (CrAT), a bidirectional mitochondrial matrix enzyme. We show here that contractile activity reverses acetylcarnitine flux in muscle, from net production and efflux at rest to net uptake and consumption during exercise. Disruption of this switch in mice with muscle-specific CrAT deficiency resulted in acetyl-CoA deficit, perturbed energy charge, and diminished exercise tolerance, whereas acetylcarnitine supplementation produced opposite outcomes in a CrAT-dependent manner. Likewise, in exercise-trained compared to untrained humans, post-exercise phosphocreatine recovery rates were positively associated with CrAT activity and coincided with dramatic shifts in muscle acetylcarnitine dynamics. These findings show acetylcarnitine serves as a critical acetyl buffer for working muscles and provide insight into potential therapeutic strategies for combatting exercise intolerance.

Authors
Seiler, SE; Koves, TR; Gooding, JR; Wong, KE; Stevens, RD; Ilkayeva, OR; Wittmann, AH; DeBalsi, KL; Davies, MN; Lindeboom, L; Schrauwen, P; Schrauwen-Hinderling, VB; Muoio, DM
MLA Citation
Seiler, SE, Koves, TR, Gooding, JR, Wong, KE, Stevens, RD, Ilkayeva, OR, Wittmann, AH, DeBalsi, KL, Davies, MN, Lindeboom, L, Schrauwen, P, Schrauwen-Hinderling, VB, and Muoio, DM. "Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise." Cell metabolism 22.1 (July 2015): 65-76.
PMID
26154055
Source
epmc
Published In
Cell Metabolism
Volume
22
Issue
1
Publish Date
2015
Start Page
65
End Page
76
DOI
10.1016/j.cmet.2015.06.003

Harnessing the Power of Integrated Mitochondrial Biology and Physiology: A Special Report on the NHLBI Mitochondria in Heart Diseases Initiative.

Mitochondrial biology is the sum of diverse phenomena from molecular profiles to physiological functions. A mechanistic understanding of mitochondria in disease development, and hence the future prospect of clinical translations, relies on a systems-level integration of expertise from multiple fields of investigation. Upon the successful conclusion of a recent National Institutes of Health, National Heart, Lung, and Blood Institute initiative on integrative mitochondrial biology in cardiovascular diseases, we reflect on the accomplishments made possible by this unique interdisciplinary collaboration effort and exciting new fronts on the study of these remarkable organelles.

Authors
Ping, P; Gustafsson, ÅB; Bers, DM; Blatter, LA; Cai, H; Jahangir, A; Kelly, D; Muoio, D; O'Rourke, B; Rabinovitch, P; Trayanova, N; Van Eyk, J; Weiss, JN; Wong, R; Schwartz Longacre, L
MLA Citation
Ping, P, Gustafsson, ÅB, Bers, DM, Blatter, LA, Cai, H, Jahangir, A, Kelly, D, Muoio, D, O'Rourke, B, Rabinovitch, P, Trayanova, N, Van Eyk, J, Weiss, JN, Wong, R, and Schwartz Longacre, L. "Harnessing the Power of Integrated Mitochondrial Biology and Physiology: A Special Report on the NHLBI Mitochondria in Heart Diseases Initiative." Circulation research 117.3 (July 2015): 234-238.
PMID
26185209
Source
epmc
Published In
Circulation Research
Volume
117
Issue
3
Publish Date
2015
Start Page
234
End Page
238
DOI
10.1161/circresaha.117.306693

Muscle-Specific Overexpression of PGC-1α Does Not Augment Metabolic Improvements in Response to Exercise and Caloric Restriction.

This study used mice with muscle-specific overexpression of PGC-1α, a transcriptional coactivator that promotes mitochondrial biogenesis, to determine whether increased oxidative potential facilitates metabolic improvements in response to lifestyle modification. MCK-PGC1α mice and nontransgenic (NT) littermates were fed a high-fat diet (HFD) for 10 weeks, followed by stepwise exposures to voluntary wheel running (HFD+Ex) and then 25% caloric restriction with exercise (Ex/CR), each for an additional 10 weeks with continued HFD. Running and CR improved weight and glucose control similarly in MCK-PGC1α and NT mice. Sedentary MCK-PGC1α mice were more susceptible to diet-induced glucose intolerance, and insulin action measured in isolated skeletal muscles remained lower in the transgenic compared with the NT group, even after Ex/CR. Comprehensive profiling of >200 metabolites and lipid intermediates revealed dramatic group-specific responses to the intervention but did not produce a lead candidate that tracked with changes in glucose tolerance irrespective of genotype. Instead, principal components analysis identified a chemically diverse metabolite cluster that correlated with multiple measures of insulin responsiveness. These findings challenge the notion that increased oxidative capacity defends whole-body energy homeostasis and suggest that the interplay between mitochondrial performance, lipotoxicity, and insulin action is more complex than previously proposed.

Authors
Wong, KE; Mikus, CR; Slentz, DH; Seiler, SE; DeBalsi, KL; Ilkayeva, OR; Crain, KI; Kinter, MT; Kien, CL; Stevens, RD; Muoio, DM
MLA Citation
Wong, KE, Mikus, CR, Slentz, DH, Seiler, SE, DeBalsi, KL, Ilkayeva, OR, Crain, KI, Kinter, MT, Kien, CL, Stevens, RD, and Muoio, DM. "Muscle-Specific Overexpression of PGC-1α Does Not Augment Metabolic Improvements in Response to Exercise and Caloric Restriction." Diabetes 64.5 (May 2015): 1532-1543.
PMID
25422105
Source
epmc
Published In
Diabetes
Volume
64
Issue
5
Publish Date
2015
Start Page
1532
End Page
1543
DOI
10.2337/db14-0827

Metabolomic analysis reveals altered skeletal muscle amino acid and fatty acid handling in obese humans.

Investigate the effects of obesity and high-fat diet (HFD) exposure on fatty acid oxidation and TCA cycle intermediates and amino acids in skeletal muscle to better characterize energy metabolism.Plasma and skeletal muscle metabolomic profiles were measured from lean and obese males before and after a 5-day HFD in the 4 h postprandial condition.At both time points, plasma short-chain acylcarnitine species (SCAC) were higher in the obese subjects, while the amino acids glycine, histidine, methionine, and citrulline were lower in skeletal muscle of obese subjects. Skeletal muscle medium-chain acylcarnitines (MCAC) C6, C8, C10:2, C10:1, C10, and C12:1 increased in obese subjects, but decreased in lean subjects, from pre- to post-HFD. Plasma content of C10:1 was also decreased in the lean but increased in the obese subjects from pre- to post-HFD. CD36 increased from pre- to post-HFD in obese but not lean subjects.Lower skeletal muscle amino acid content and accumulation of plasma SCAC in obese subjects could reflect increased anaplerosis for TCA cycle intermediates, while accumulation of MCAC suggests limitations in β-oxidation. These measures may be important markers of or contributors to dysregulated metabolism observed in skeletal muscle of obese humans.

Authors
Baker, PR; Boyle, KE; Koves, TR; Ilkayeva, OR; Muoio, DM; Houmard, JA; Friedman, JE
MLA Citation
Baker, PR, Boyle, KE, Koves, TR, Ilkayeva, OR, Muoio, DM, Houmard, JA, and Friedman, JE. "Metabolomic analysis reveals altered skeletal muscle amino acid and fatty acid handling in obese humans." Obesity (Silver Spring, Md.) 23.5 (May 2015): 981-988.
PMID
25864501
Source
epmc
Published In
Obesity (Silver Spring, Md.)
Volume
23
Issue
5
Publish Date
2015
Start Page
981
End Page
988
DOI
10.1002/oby.21046

Women in Metabolism: Part I

MLA Citation
"Women in Metabolism: Part I." Cell Metabolism 21.5 (May 2015): 654-657.
Source
crossref
Published In
Cell Metabolism
Volume
21
Issue
5
Publish Date
2015
Start Page
654
End Page
657
DOI
10.1016/j.cmet.2015.04.017

Metabolomic analysis reveals altered skeletal muscle amino acid and fatty acid handling in obese humans

Authors
Baker, PR; Boyle, KE; Koves, TR; Ilkayeva, OR; Muoio, DM; Houmard, JA; Friedman, JE
MLA Citation
Baker, PR, Boyle, KE, Koves, TR, Ilkayeva, OR, Muoio, DM, Houmard, JA, and Friedman, JE. "Metabolomic analysis reveals altered skeletal muscle amino acid and fatty acid handling in obese humans." Obesity 23.5 (May 2015): 981-988.
Source
crossref
Published In
Obesity (Silver Spring, Md.)
Volume
23
Issue
5
Publish Date
2015
Start Page
981
End Page
988
DOI
10.1002/oby.21046

Pyruvate dehydrogenase complex and nicotinamide nucleotide transhydrogenase constitute an energy-consuming redox circuit.

Cellular proteins rely on reversible redox reactions to establish and maintain biological structure and function. How redox catabolic (NAD+/NADH) and anabolic (NADP+/NADPH) processes integrate during metabolism to maintain cellular redox homoeostasis, however, is unknown. The present work identifies a continuously cycling mitochondrial membrane potential (ΔΨm)-dependent redox circuit between the pyruvate dehydrogenase complex (PDHC) and nicotinamide nucleotide transhydrogenase (NNT). PDHC is shown to produce H2O2 in relation to reducing pressure within the complex. The H2O2 produced, however, is effectively masked by a continuously cycling redox circuit that links, via glutathione/thioredoxin, to NNT, which catalyses the regeneration of NADPH from NADH at the expense of ΔΨm. The net effect is an automatic fine-tuning of NNT-mediated energy expenditure to metabolic balance at the level of PDHC. In mitochondria, genetic or pharmacological disruptions in the PDHC-NNT redox circuit negate counterbalance changes in energy expenditure. At the whole animal level, mice lacking functional NNT (C57BL/6J) are characterized by lower energy-expenditure rates, consistent with their well-known susceptibility to diet-induced obesity. These findings suggest the integration of redox sensing of metabolic balance with compensatory changes in energy expenditure provides a potential mechanism by which cellular redox homoeostasis is maintained and body weight is defended during periods of positive and negative energy balance.

Authors
Fisher-Wellman, KH; Lin, C-T; Ryan, TE; Reese, LR; Gilliam, LAA; Cathey, BL; Lark, DS; Smith, CD; Muoio, DM; Neufer, PD
MLA Citation
Fisher-Wellman, KH, Lin, C-T, Ryan, TE, Reese, LR, Gilliam, LAA, Cathey, BL, Lark, DS, Smith, CD, Muoio, DM, and Neufer, PD. "Pyruvate dehydrogenase complex and nicotinamide nucleotide transhydrogenase constitute an energy-consuming redox circuit." The Biochemical journal 467.2 (April 2015): 271-280.
PMID
25643703
Source
epmc
Published In
The Biochemical journal
Volume
467
Issue
2
Publish Date
2015
Start Page
271
End Page
280
DOI
10.1042/bj20141447

Abstract PR09: A genome-wide RNAi screen reveals a protective role of decreased lipogenesis under hypoxia

Authors
Keenan, MM; Liu, B; Wu, J; Cyr, D; Lucas, J; Muoio, DM; Kim, SY; Chi, J-T
MLA Citation
Keenan, MM, Liu, B, Wu, J, Cyr, D, Lucas, J, Muoio, DM, Kim, SY, and Chi, J-T. "Abstract PR09: A genome-wide RNAi screen reveals a protective role of decreased lipogenesis under hypoxia." January 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
1 Supplement
Publish Date
2015
Start Page
PR09
End Page
PR09
DOI
10.1158/1538-7445.CHTME14-PR09

Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.

The impaired capacity of skeletal muscle to switch between the oxidation of fatty acid (FA) and glucose is linked to disordered metabolic homeostasis. To understand how muscle FA oxidation affects systemic glucose, we studied mice with a skeletal muscle-specific deficiency of long-chain acyl-CoA synthetase (ACSL)1. ACSL1 deficiency caused a 91% loss of ACSL-specific activity and a 60-85% decrease in muscle FA oxidation. Acsl1(M-/-) mice were more insulin sensitive, and, during an overnight fast, their respiratory exchange ratio was higher, indicating greater glucose use. During endurance exercise, Acsl1(M-/-) mice ran only 48% as far as controls. At the time that Acsl1(M-/-) mice were exhausted but control mice continued to run, liver and muscle glycogen and triacylglycerol stores were similar in both genotypes; however, plasma glucose concentrations in Acsl1(M-/-) mice were ∼40 mg/dL, whereas glucose concentrations in controls were ∼90 mg/dL. Excess use of glucose and the likely use of amino acids for fuel within muscle depleted glucose reserves and diminished substrate availability for hepatic gluconeogenesis. Surprisingly, the content of muscle acyl-CoA at exhaustion was markedly elevated, indicating that acyl-CoAs synthesized by other ACSL isoforms were not available for β-oxidation. This compartmentalization of acyl-CoAs resulted in both an excessive glucose requirement and severely compromised systemic glucose homeostasis.

Authors
Li, LO; Grevengoed, TJ; Paul, DS; Ilkayeva, O; Koves, TR; Pascual, F; Newgard, CB; Muoio, DM; Coleman, RA
MLA Citation
Li, LO, Grevengoed, TJ, Paul, DS, Ilkayeva, O, Koves, TR, Pascual, F, Newgard, CB, Muoio, DM, and Coleman, RA. "Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis." Diabetes 64.1 (January 2015): 23-35.
PMID
25071025
Source
epmc
Published In
Diabetes
Volume
64
Issue
1
Publish Date
2015
Start Page
23
End Page
35
DOI
10.2337/db13-1070

The good in fat

Authors
Muoio, DM; Newgard, CB
MLA Citation
Muoio, DM, and Newgard, CB. "The good in fat." Nature 516.729 (December 4, 2014): 49-50.
Source
scopus
Published In
Nature
Volume
516
Issue
729
Publish Date
2014
Start Page
49
End Page
50
DOI
10.1038/nature14070

Diabetes: The good in fat

Authors
Muoio, DM; Newgard, CB
MLA Citation
Muoio, DM, and Newgard, CB. "Diabetes: The good in fat." Nature 516.7529 (December 4, 2014): 49-50.
Source
scopus
Published In
Nature
Volume
516
Issue
7529
Publish Date
2014
Start Page
49
End Page
50
DOI
10.1038/nature14070

Diabetes: The good in fat.

Authors
Muoio, DM; Newgard, CB
MLA Citation
Muoio, DM, and Newgard, CB. "Diabetes: The good in fat." Nature 516.7529 (December 2014): 49-50.
PMID
25409152
Source
epmc
Published In
Nature
Volume
516
Issue
7529
Publish Date
2014
Start Page
49
End Page
50
DOI
10.1038/nature14070

Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock.

Normal energy metabolism is characterized by periodic shifts in glucose and fat oxidation, as the mitochondrial machinery responsible for carbon combustion switches freely between alternative fuels according to physiological and nutritional circumstances. These transitions in fuel choice are orchestrated by an intricate network of metabolic and cell signaling events that enable exquisite crosstalk and cooperation between competing substrates to maintain energy and glucose homeostasis. By contrast, obesity-related cardiometabolic diseases are increasingly recognized as disorders of metabolic inflexibility, in which nutrient overload and heightened substrate competition result in mitochondrial indecision, impaired fuel switching, and energy dysregulation. This Perspective offers a speculative view on the molecular origins and pathophysiological consequences of metabolic inflexibility.

Authors
Muoio, DM
MLA Citation
Muoio, DM. "Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock." Cell 159.6 (December 2014): 1253-1262.
PMID
25480291
Source
epmc
Published In
Cell
Volume
159
Issue
6
Publish Date
2014
Start Page
1253
End Page
1262
DOI
10.1016/j.cell.2014.11.034

Downregulation of carnitine acyl-carnitine translocase by miRNAs 132 and 212 amplifies glucose-stimulated insulin secretion.

We previously demonstrated that micro-RNAs (miRNAs) 132 and 212 are differentially upregulated in response to obesity in two mouse strains that differ in their susceptibility to obesity-induced diabetes. Here we show the overexpression of miRNAs 132 and 212 enhances insulin secretion (IS) in response to glucose and other secretagogues including nonfuel stimuli. We determined that carnitine acyl-carnitine translocase (CACT; Slc25a20) is a direct target of these miRNAs. CACT is responsible for transporting long-chain acyl-carnitines into the mitochondria for β-oxidation. Small interfering RNA-mediated knockdown of CACT in β-cells led to the accumulation of fatty acyl-carnitines and enhanced IS. The addition of long-chain fatty acyl-carnitines promoted IS from rat insulinoma β-cells (INS-1) as well as primary mouse islets. The effect on INS-1 cells was augmented in response to suppression of CACT. A nonhydrolyzable ether analog of palmitoyl-carnitine stimulated IS, showing that β-oxidation of palmitoyl-carnitine is not required for its stimulation of IS. These studies establish a link between miRNA-dependent regulation of CACT and fatty acyl-carnitine-mediated regulation of IS.

Authors
Soni, MS; Rabaglia, ME; Bhatnagar, S; Shang, J; Ilkayeva, O; Mynatt, R; Zhou, Y-P; Schadt, EE; Thornberry, NA; Muoio, DM; Keller, MP; Attie, AD
MLA Citation
Soni, MS, Rabaglia, ME, Bhatnagar, S, Shang, J, Ilkayeva, O, Mynatt, R, Zhou, Y-P, Schadt, EE, Thornberry, NA, Muoio, DM, Keller, MP, and Attie, AD. "Downregulation of carnitine acyl-carnitine translocase by miRNAs 132 and 212 amplifies glucose-stimulated insulin secretion." Diabetes 63.11 (November 2014): 3805-3814.
PMID
24969106
Source
epmc
Published In
Diabetes
Volume
63
Issue
11
Publish Date
2014
Start Page
3805
End Page
3814
DOI
10.2337/db13-1677

Metabolite signatures of exercise training in human skeletal muscle relate to mitochondrial remodelling and cardiometabolic fitness.

Targeted metabolomic and transcriptomic approaches were used to evaluate the relationship between skeletal muscle metabolite signatures, gene expression profiles and clinical outcomes in response to various exercise training interventions. We hypothesised that changes in mitochondrial metabolic intermediates would predict improvements in clinical risk factors, thereby offering novel insights into potential mechanisms.Subjects at risk of metabolic disease were randomised to 6 months of inactivity or one of five aerobic and/or resistance training programmes (n = 112). Pre/post-intervention assessments included cardiorespiratory fitness ([Formula: see text]), serum triacylglycerols (TGs) and insulin sensitivity (SI). In this secondary analysis, muscle biopsy specimens were used for targeted mass spectrometry-based analysis of metabolic intermediates and measurement of mRNA expression of genes involved in metabolism.Exercise regimens with the largest energy expenditure produced robust increases in muscle concentrations of even-chain acylcarnitines (median 37-488%), which correlated positively with increased expression of genes involved in muscle uptake and oxidation of fatty acids. Along with free carnitine, the aforementioned acylcarnitine metabolites were related to improvements in [Formula: see text], TGs and SI (R = 0.20-0.31, p < 0.05). Muscle concentrations of the tricarboxylic acid cycle intermediates succinate and succinylcarnitine (R = 0.39 and 0.24, p < 0.05) emerged as the strongest correlates of SI.The metabolic signatures of exercise-trained skeletal muscle reflected reprogramming of mitochondrial function and intermediary metabolism and correlated with changes in cardiometabolic fitness. Succinate metabolism and the succinate dehydrogenase complex emerged as a potential regulatory node that intersects with whole-body insulin sensitivity. This study identifies new avenues for mechanistic research aimed at understanding the health benefits of physical activity. Trial registration ClinicalTrials.gov NCT00200993 and NCT00275145 Funding This work was supported by the National Heart, Lung, and Blood Institute (National Institutes of Health), National Institute on Aging (National Institutes of Health) and National Institute of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health).

Authors
Huffman, KM; Koves, TR; Hubal, MJ; Abouassi, H; Beri, N; Bateman, LA; Stevens, RD; Ilkayeva, OR; Hoffman, EP; Muoio, DM; Kraus, WE
MLA Citation
Huffman, KM, Koves, TR, Hubal, MJ, Abouassi, H, Beri, N, Bateman, LA, Stevens, RD, Ilkayeva, OR, Hoffman, EP, Muoio, DM, and Kraus, WE. "Metabolite signatures of exercise training in human skeletal muscle relate to mitochondrial remodelling and cardiometabolic fitness." Diabetologia 57.11 (November 2014): 2282-2295.
PMID
25091629
Source
epmc
Published In
Diabetologia
Volume
57
Issue
11
Publish Date
2014
Start Page
2282
End Page
2295
DOI
10.1007/s00125-014-3343-4

Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach.

An unbiased systems approach was used to define energy metabolic events that occur during the pathological cardiac remodeling en route to heart failure (HF).Combined myocardial transcriptomic and metabolomic profiling were conducted in a well-defined mouse model of HF that allows comparative assessment of compensated and decompensated (HF) forms of cardiac hypertrophy because of pressure overload. The pressure overload data sets were also compared with the myocardial transcriptome and metabolome for an adaptive (physiological) form of cardiac hypertrophy because of endurance exercise training. Comparative analysis of the data sets led to the following conclusions: (1) expression of most genes involved in mitochondrial energy transduction were not significantly changed in the hypertrophied or failing heart, with the notable exception of a progressive downregulation of transcripts encoding proteins and enzymes involved in myocyte fatty acid transport and oxidation during the development of HF; (2) tissue metabolite profiles were more broadly regulated than corresponding metabolic gene regulatory changes, suggesting significant regulation at the post-transcriptional level; (3) metabolomic signatures distinguished pathological and physiological forms of cardiac hypertrophy and served as robust markers for the onset of HF; and (4) the pattern of metabolite derangements in the failing heart suggests bottlenecks of carbon substrate flux into the Krebs cycle.Mitochondrial energy metabolic derangements that occur during the early development of pressure overload-induced HF involve both transcriptional and post-transcriptional events. A subset of the myocardial metabolomic profile robustly distinguished pathological and physiological cardiac remodeling.

Authors
Lai, L; Leone, TC; Keller, MP; Martin, OJ; Broman, AT; Nigro, J; Kapoor, K; Koves, TR; Stevens, R; Ilkayeva, OR; Vega, RB; Attie, AD; Muoio, DM; Kelly, DP
MLA Citation
Lai, L, Leone, TC, Keller, MP, Martin, OJ, Broman, AT, Nigro, J, Kapoor, K, Koves, TR, Stevens, R, Ilkayeva, OR, Vega, RB, Attie, AD, Muoio, DM, and Kelly, DP. "Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach." Circulation. Heart failure 7.6 (November 2014): 1022-1031.
PMID
25236884
Source
epmc
Published In
Circulation: Heart Failure
Volume
7
Issue
6
Publish Date
2014
Start Page
1022
End Page
1031
DOI
10.1161/circheartfailure.114.001469

Long-echo time MR spectroscopy for skeletal muscle acetylcarnitine detection.

Animal models suggest that acetylcarnitine production is essential for maintaining metabolic flexibility and insulin sensitivity. Because current methods to detect acetylcarnitine involve biopsy of the tissue of interest, noninvasive alternatives to measure acetylcarnitine concentrations could facilitate our understanding of its physiological relevance in humans. Here, we investigated the use of long-echo time (TE) proton magnetic resonance spectroscopy (1H-MRS) to measure skeletal muscle acetylcarnitine concentrations on a clinical 3T scanner. We applied long-TE 1H-MRS to measure acetylcarnitine in endurance-trained athletes, lean and obese sedentary subjects, and type 2 diabetes mellitus (T2DM) patients to cover a wide spectrum in insulin sensitivity. A long-TE 1H-MRS protocol was implemented for successful detection of skeletal muscle acetylcarnitine in these individuals. There were pronounced differences in insulin sensitivity, as measured by hyperinsulinemic-euglycemic clamp, and skeletal muscle mitochondrial function, as measured by phosphorus-MRS (31P-MRS), across groups. Insulin sensitivity and mitochondrial function were highest in trained athletes and lowest in T2DM patients. Skeletal muscle acetylcarnitine concentration showed a reciprocal distribution, with mean acetylcarnitine concentration correlating with mean insulin sensitivity in each group. These results demonstrate that measuring acetylcarnitine concentrations with 1H-MRS is feasible on clinical MR scanners and support the hypothesis that T2DM patients are characterized by a decreased formation of acetylcarnitine, possibly underlying decreased insulin sensitivity.

Authors
Lindeboom, L; Nabuurs, CI; Hoeks, J; Brouwers, B; Phielix, E; Kooi, ME; Hesselink, MKC; Wildberger, JE; Stevens, RD; Koves, T; Muoio, DM; Schrauwen, P; Schrauwen-Hinderling, VB
MLA Citation
Lindeboom, L, Nabuurs, CI, Hoeks, J, Brouwers, B, Phielix, E, Kooi, ME, Hesselink, MKC, Wildberger, JE, Stevens, RD, Koves, T, Muoio, DM, Schrauwen, P, and Schrauwen-Hinderling, VB. "Long-echo time MR spectroscopy for skeletal muscle acetylcarnitine detection." The Journal of clinical investigation 124.11 (November 2014): 4915-4925.
PMID
25271624
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
11
Publish Date
2014
Start Page
4915
End Page
4925
DOI
10.1172/jci74830

Treatment with the 3-ketoacyl-CoA thiolase inhibitor trimetazidine does not exacerbate whole-body insulin resistance in obese mice.

There is a growing need to understand the underlying mechanisms involved in the progression of cardiovascular disease during obesity and diabetes. Although inhibition of fatty acid oxidation has been proposed as a novel approach to treat ischemic heart disease and heart failure, reduced muscle fatty acid oxidation rates may contribute to the development of obesity-associated insulin resistance. Our aim was to determine whether treatment with the antianginal agent trimetazidine, which inhibits fatty acid oxidation in the heart secondary to inhibition of 3-ketoacyl-CoA thiolase (3-KAT), may have off-target effects on glycemic control in obesity. We fed C57BL/6NCrl mice a high-fat diet (HFD) for 10 weeks before a 22-day treatment with the 3-KAT inhibitor trimetazidine (15 mg/kg per day). Insulin resistance was assessed via glucose/insulin tolerance testing, and lipid metabolite content was assessed in gastrocnemius muscle. Trimetazidine-treatment led to a mild shift in substrate preference toward carbohydrates as an oxidative fuel source in obese mice, evidenced by an increase in the respiratory exchange ratio. This shift in metabolism was accompanied by an accumulation of long-chain acyl-CoA and a trend to an increase in triacylglycerol content in gastrocnemius muscle, but did not exacerbate HFD-induced insulin resistance compared with control-treated mice. It is noteworthy that trimetazidine treatment reduced palmitate oxidation rates in the isolated working mouse heart and neonatal cardiomyocytes but not C2C12 skeletal myotubes. Our findings demonstrate that trimetazidine therapy does not adversely affect HFD-induced insulin resistance, suggesting that treatment with trimetazidine would not worsen glycemic control in obese patients with angina.

Authors
Ussher, JR; Keung, W; Fillmore, N; Koves, TR; Mori, J; Zhang, L; Lopaschuk, DG; Ilkayeva, OR; Wagg, CS; Jaswal, JS; Muoio, DM; Lopaschuk, GD
MLA Citation
Ussher, JR, Keung, W, Fillmore, N, Koves, TR, Mori, J, Zhang, L, Lopaschuk, DG, Ilkayeva, OR, Wagg, CS, Jaswal, JS, Muoio, DM, and Lopaschuk, GD. "Treatment with the 3-ketoacyl-CoA thiolase inhibitor trimetazidine does not exacerbate whole-body insulin resistance in obese mice." The Journal of pharmacology and experimental therapeutics 349.3 (June 2014): 487-496.
PMID
24700885
Source
epmc
Published In
The Journal of pharmacology and experimental therapeutics
Volume
349
Issue
3
Publish Date
2014
Start Page
487
End Page
496
DOI
10.1124/jpet.114.214197

Obesity and lipid stress inhibit carnitine acetyltransferase activity.

Carnitine acetyltransferase (CrAT) is a mitochondrial matrix enzyme that catalyzes the interconversion of acetyl-CoA and acetylcarnitine. Emerging evidence suggests that this enzyme functions as a positive regulator of total body glucose tolerance and muscle activity of pyruvate dehydrogenase (PDH), a mitochondrial enzyme complex that promotes glucose oxidation and is feedback inhibited by acetyl-CoA. Here, we used tandem mass spectrometry-based metabolic profiling to identify a negative relationship between CrAT activity and muscle content of lipid intermediates. CrAT specific activity was diminished in muscles from obese and diabetic rodents despite increased protein abundance. This reduction in enzyme activity was accompanied by muscle accumulation of long-chain acylcarnitines (LCACs) and acyl-CoAs and a decline in the acetylcarnitine/acetyl-CoA ratio. In vitro assays demonstrated that palmitoyl-CoA acts as a direct mixed-model inhibitor of CrAT. Similarly, in primary human myocytes grown in culture, nutritional and genetic manipulations that promoted mitochondrial influx of fatty acids resulted in accumulation of LCACs but a pronounced decrease of CrAT-derived short-chain acylcarnitines. These results suggest that lipid-induced antagonism of CrAT might contribute to decreased PDH activity and glucose disposal in the context of obesity and diabetes.

Authors
Seiler, SE; Martin, OJ; Noland, RC; Slentz, DH; DeBalsi, KL; Ilkayeva, OR; An, J; Newgard, CB; Koves, TR; Muoio, DM
MLA Citation
Seiler, SE, Martin, OJ, Noland, RC, Slentz, DH, DeBalsi, KL, Ilkayeva, OR, An, J, Newgard, CB, Koves, TR, and Muoio, DM. "Obesity and lipid stress inhibit carnitine acetyltransferase activity." J Lipid Res 55.4 (April 2014): 635-644.
PMID
24395925
Source
pubmed
Published In
Journal of lipid research
Volume
55
Issue
4
Publish Date
2014
Start Page
635
End Page
644
DOI
10.1194/jlr.M043448

Dietary intake of palmitate and oleate has broad impact on systemic and tissue lipid profiles in humans

Background: Epidemiologic evidence has suggested that diets with a high ratio of palmitic acid (PA) to oleic acid (OA) increase risk of cardiovascular disease (CVD). Objective: To gain additional insights into the relative effect of dietary fatty acids and their metabolism on CVD risk, we sought to identify a metabolomic signature that tracks with diet-induced changes in blood lipid concentrations and whole-body fat oxidation. Design: We applied comprehensive metabolomic profiling tools to biological specimens collected from 18 healthy adults enrolled in a crossover trial that compared a 3-wk high-palmitic acid (HPA) with a low-palmitic acid and high-oleic acid (HOA) diet. Results: A principal components analysis of the data set including 329 variables measured in 15 subjects in the fasted state identified one factor, the principal components analysis factor in the fasted state (PCF1-Fasted), which was heavily weighted by the PA:OA ratio of serum and muscle lipids, that was affected by diet (P < 0.0001; HPA greater than HOA). One other factor, the additional principal components analysis factor in the fasted state (PCF2-Fasted), reflected a wide range of acylcarnitines and was affected by diet in women only (P = 0.0198; HPA greater than HOA). HOA lowered the ratio of serum low-density lipoprotein to high-density lipoprotein (LDL:HDL) in men and women, and adjustment for the PCF1-Fasted abolished the effect. In women only, adjustment for the PCF2-Fasted eliminated the HOA-diet effect on serum total- and LDL-cholesterol concentrations. The respiratory exchange ratio in the fasted state was lower with the HPA diet (P = 0.04), and the diet effect was eliminated after adjustment for the PCF1-Fasted. The messenger RNA expression of the cholesterol regulatory gene insulin- induced gene-1 was higher with the HOA diet (P = 0.008). Conclusions: These results suggest that replacing dietary PAwith OA reduces the blood LDL concentration and whole-body fat oxidation by modifying the saturation index of circulating and tissue lipids. In women, these effects are also associated with a higher production and accumulation of acylcarnitines, possibly reflecting a shift in fat catabolism. © 2014 American Society for Nutrition.

Authors
Kien, CL; Bunn, JY; Stevens, R; Bain, J; Ikayeva, O; Crain, K; Koves, TR; Muoio, DM
MLA Citation
Kien, CL, Bunn, JY, Stevens, R, Bain, J, Ikayeva, O, Crain, K, Koves, TR, and Muoio, DM. "Dietary intake of palmitate and oleate has broad impact on systemic and tissue lipid profiles in humans." American Journal of Clinical Nutrition 99.3 (March 1, 2014): 436-445.
Source
scopus
Published In
American Journal of Clinical Nutrition
Volume
99
Issue
3
Publish Date
2014
Start Page
436
End Page
445
DOI
10.3945/ajcn.113.070557

Dietary intake of palmitate and oleate has broad impact on systemic and tissue lipid profiles in humans.

Epidemiologic evidence has suggested that diets with a high ratio of palmitic acid (PA) to oleic acid (OA) increase risk of cardiovascular disease (CVD).To gain additional insights into the relative effect of dietary fatty acids and their metabolism on CVD risk, we sought to identify a metabolomic signature that tracks with diet-induced changes in blood lipid concentrations and whole-body fat oxidation.We applied comprehensive metabolomic profiling tools to biological specimens collected from 18 healthy adults enrolled in a crossover trial that compared a 3-wk high-palmitic acid (HPA) with a low-palmitic acid and high-oleic acid (HOA) diet.A principal components analysis of the data set including 329 variables measured in 15 subjects in the fasted state identified one factor, the principal components analysis factor in the fasted state (PCF1-Fasted), which was heavily weighted by the PA:OA ratio of serum and muscle lipids, that was affected by diet (P < 0.0001; HPA greater than HOA). One other factor, the additional principal components analysis factor in the fasted state (PCF2-Fasted), reflected a wide range of acylcarnitines and was affected by diet in women only (P = 0.0198; HPA greater than HOA). HOA lowered the ratio of serum low-density lipoprotein to high-density lipoprotein (LDL:HDL) in men and women, and adjustment for the PCF1-Fasted abolished the effect. In women only, adjustment for the PCF2-Fasted eliminated the HOA-diet effect on serum total- and LDL-cholesterol concentrations. The respiratory exchange ratio in the fasted state was lower with the HPA diet (P = 0.04), and the diet effect was eliminated after adjustment for the PCF1-Fasted. The messenger RNA expression of the cholesterol regulatory gene insulin-induced gene-1 was higher with the HOA diet (P = 0.008).These results suggest that replacing dietary PA with OA reduces the blood LDL concentration and whole-body fat oxidation by modifying the saturation index of circulating and tissue lipids. In women, these effects are also associated with a higher production and accumulation of acylcarnitines, possibly reflecting a shift in fat catabolism.

Authors
Kien, CL; Bunn, JY; Stevens, R; Bain, J; Ikayeva, O; Crain, K; Koves, TR; Muoio, DM
MLA Citation
Kien, CL, Bunn, JY, Stevens, R, Bain, J, Ikayeva, O, Crain, K, Koves, TR, and Muoio, DM. "Dietary intake of palmitate and oleate has broad impact on systemic and tissue lipid profiles in humans." The American journal of clinical nutrition 99.3 (March 2014): 436-445.
PMID
24429541
Source
epmc
Published In
American Journal of Clinical Nutrition
Volume
99
Issue
3
Publish Date
2014
Start Page
436
End Page
445
DOI
10.3945/ajcn.113.070557

Targeted metabolomics connects thioredoxin-interacting protein (TXNIP) to mitochondrial fuel selection and regulation of specific oxidoreductase enzymes in skeletal muscle.

Thioredoxin-interacting protein (TXNIP) is an α-arrestin family member involved in redox sensing and metabolic control. Growing evidence links TXNIP to mitochondrial function, but the molecular nature of this relationship has remained poorly defined. Herein, we employed targeted metabolomics and comprehensive bioenergetic analyses to evaluate oxidative metabolism and respiratory kinetics in mouse models of total body (TKO) and skeletal muscle-specific (TXNIP(SKM-/-)) Txnip deficiency. Compared with littermate controls, both TKO and TXNIP(SKM-/-) mice had reduced exercise tolerance in association with muscle-specific impairments in substrate oxidation. Oxidative insufficiencies in TXNIP null muscles were not due to perturbations in mitochondrial mass, the electron transport chain, or emission of reactive oxygen species. Instead, metabolic profiling analyses led to the discovery that TXNIP deficiency causes marked deficits in enzymes required for catabolism of branched chain amino acids, ketones, and lactate, along with more modest reductions in enzymes of β-oxidation and the tricarboxylic acid cycle. The decrements in enzyme activity were accompanied by comparable deficits in protein abundance without changes in mRNA expression, implying dysregulation of protein synthesis or stability. Considering that TXNIP expression increases in response to starvation, diabetes, and exercise, these findings point to a novel role for TXNIP in coordinating mitochondrial fuel switching in response to nutrient availability.

Authors
DeBalsi, KL; Wong, KE; Koves, TR; Slentz, DH; Seiler, SE; Wittmann, AH; Ilkayeva, OR; Stevens, RD; Perry, CGR; Lark, DS; Hui, ST; Szweda, L; Neufer, PD; Muoio, DM
MLA Citation
DeBalsi, KL, Wong, KE, Koves, TR, Slentz, DH, Seiler, SE, Wittmann, AH, Ilkayeva, OR, Stevens, RD, Perry, CGR, Lark, DS, Hui, ST, Szweda, L, Neufer, PD, and Muoio, DM. "Targeted metabolomics connects thioredoxin-interacting protein (TXNIP) to mitochondrial fuel selection and regulation of specific oxidoreductase enzymes in skeletal muscle." The Journal of biological chemistry 289.12 (March 2014): 8106-8120.
PMID
24482226
Source
epmc
Published In
The Journal of biological chemistry
Volume
289
Issue
12
Publish Date
2014
Start Page
8106
End Page
8120
DOI
10.1074/jbc.m113.511535

A role for peroxisome proliferator-activated receptor γ coactivator-1 in the control of mitochondrial dynamics during postnatal cardiac growth.

RATIONALE: Increasing evidence has shown that proper control of mitochondrial dynamics (fusion and fission) is required for high-capacity ATP production in the heart. Transcriptional coactivators, peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) α and PGC-1β, have been shown to regulate mitochondrial biogenesis in the heart at the time of birth. The function of PGC-1 coactivators in the heart after birth has been incompletely understood. OBJECTIVE: Our aim was to assess the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts in mice. METHODS AND RESULTS: Conditional gene targeting was used in mice to explore the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts. Marked mitochondrial structural derangements were observed in hearts of PGC-1α/β-deficient mice during postnatal growth, including fragmentation and elongation, associated with the development of a lethal cardiomyopathy. The expression of genes involved in mitochondrial fusion (Mfn1, Opa1) and fission (Drp1, Fis1) was altered in the hearts of PGC-1α/β-deficient mice. PGC-lα was shown to directly regulate Mfn1 gene transcription by coactivating the estrogen-related receptor α on a conserved DNA element. Surprisingly, PGC-1α/β deficiency in the adult heart did not result in evidence of abnormal mitochondrial dynamics or heart failure. However, transcriptional profiling demonstrated that PGC-1 coactivators are required for high-level expression of nuclear- and mitochondrial-encoded genes involved in mitochondrial dynamics and energy transduction in the adult heart. CONCLUSIONS: These results reveal distinct developmental stage-specific programs involved in cardiac mitochondrial dynamics.

Authors
Martin, OJ; Lai, L; Soundarapandian, MM; Leone, TC; Zorzano, A; Keller, MP; Attie, AD; Muoio, DM; Kelly, DP
MLA Citation
Martin, OJ, Lai, L, Soundarapandian, MM, Leone, TC, Zorzano, A, Keller, MP, Attie, AD, Muoio, DM, and Kelly, DP. "A role for peroxisome proliferator-activated receptor γ coactivator-1 in the control of mitochondrial dynamics during postnatal cardiac growth." Circ Res 114.4 (February 14, 2014): 626-636.
PMID
24366168
Source
pubmed
Published In
Circulation Research
Volume
114
Issue
4
Publish Date
2014
Start Page
626
End Page
636
DOI
10.1161/CIRCRESAHA.114.302562

A role for peroxisome proliferator-activated receptor γ coactivator-1 in the control of mitochondrial dynamics during postnatal cardiac growth

RATIONALE:: Increasing evidence has shown that proper control of mitochondrial dynamics (fusion and fission) is required for high-capacity ATP production in the heart. Transcriptional coactivators, peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) α and PGC-1β, have been shown to regulate mitochondrial biogenesis in the heart at the time of birth. The function of PGC-1 coactivators in the heart after birth has been incompletely understood. OBJECTIVE:: Our aim was to assess the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts in mice. METHODS AND RESULTS:: Conditional gene targeting was used in mice to explore the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts. Marked mitochondrial structural derangements were observed in hearts of PGC-1α/β-deficient mice during postnatal growth, including fragmentation and elongation, associated with the development of a lethal cardiomyopathy. The expression of genes involved in mitochondrial fusion (Mfn1, Opa1) and fission (Drp1, Fis1) was altered in the hearts of PGC-1α/β-deficient mice. PGC-lα was shown to directly regulate Mfn1 gene transcription by coactivating the estrogen-related receptor α on a conserved DNA element. Surprisingly, PGC-1α/β deficiency in the adult heart did not result in evidence of abnormal mitochondrial dynamics or heart failure. However, transcriptional profiling demonstrated that PGC-1 coactivators are required for high-level expression of nuclear- and mitochondrial-encoded genes involved in mitochondrial dynamics and energy transduction in the adult heart. CONCLUSIONS:: These results reveal distinct developmental stage-specific programs involved in cardiac mitochondrial dynamics. © 2014 American Heart Association, Inc.

Authors
Martin, OJ; Lai, L; Soundarapandian, MM; Leone, TC; Zorzano, A; Keller, MP; Attie, AD; Muoio, DM; Kelly, DP
MLA Citation
Martin, OJ, Lai, L, Soundarapandian, MM, Leone, TC, Zorzano, A, Keller, MP, Attie, AD, Muoio, DM, and Kelly, DP. "A role for peroxisome proliferator-activated receptor γ coactivator-1 in the control of mitochondrial dynamics during postnatal cardiac growth." Circulation Research 114.4 (February 14, 2014): 626-636.
Source
scopus
Published In
Circulation Research
Volume
114
Issue
4
Publish Date
2014
Start Page
626
End Page
636
DOI
10.1161/CIRCRESAHA.114.302562

Metabolite signatures of exercise training in human skeletal muscle relate to mitochondrial remodelling and cardiometabolic fitness

© 2014, Springer-Verlag Berlin Heidelberg.Methods: Subjects at risk of metabolic disease were randomised to 6 months of inactivity or one of five aerobic and/or resistance training programmes (n = 112). Pre/post-intervention assessments included cardiorespiratory fitness (V⋅ O2peak), serum triacylglycerols (TGs) and insulin sensitivity (SI). In this secondary analysis, muscle biopsy specimens were used for targeted mass spectrometry-based analysis of metabolic intermediates and measurement of mRNA expression of genes involved in metabolism.Results: Exercise regimens with the largest energy expenditure produced robust increases in muscle concentrations of even-chain acylcarnitines (median 37–488%), which correlated positively with increased expression of genes involved in muscle uptake and oxidation of fatty acids. Along with free carnitine, the aforementioned acylcarnitine metabolites were related to improvements in V⋅ O2peak, TGs and SI (R = 0.20–0.31, p < 0.05). Muscle concentrations of the tricarboxylic acid cycle intermediates succinate and succinylcarnitine (R = 0.39 and 0.24, p < 0.05) emerged as the strongest correlates of SI.Conclusions/interpretation: The metabolic signatures of exercise-trained skeletal muscle reflected reprogramming of mitochondrial function and intermediary metabolism and correlated with changes in cardiometabolic fitness. Succinate metabolism and the succinate dehydrogenase complex emerged as a potential regulatory node that intersects with whole-body insulin sensitivity. This study identifies new avenues for mechanistic research aimed at understanding the health benefits of physical activity.Trial registration ClinicalTrials.gov NCT00200993 and NCT00275145Funding This work was supported by the National Heart, Lung, and Blood Institute (National Institutes of Health), National Institute on Aging (National Institutes of Health) and National Institute of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health).Aims/hypothesis: Targeted metabolomic and transcriptomic approaches were used to evaluate the relationship between skeletal muscle metabolite signatures, gene expression profiles and clinical outcomes in response to various exercise training interventions. We hypothesised that changes in mitochondrial metabolic intermediates would predict improvements in clinical risk factors, thereby offering novel insights into potential mechanisms.

Authors
Huffman, KM; Koves, TR; Hubal, MJ; Abouassi, H; Beri, N; Bateman, LA; Stevens, RD; Ilkayeva, OR; Hoffman, EP; Muoio, DM; Kraus, WE
MLA Citation
Huffman, KM, Koves, TR, Hubal, MJ, Abouassi, H, Beri, N, Bateman, LA, Stevens, RD, Ilkayeva, OR, Hoffman, EP, Muoio, DM, and Kraus, WE. "Metabolite signatures of exercise training in human skeletal muscle relate to mitochondrial remodelling and cardiometabolic fitness." Diabetologia 57.11 (January 1, 2014): 2282-2295.
Source
scopus
Published In
Diabetologia
Volume
57
Issue
11
Publish Date
2014
Start Page
2282
End Page
2295
DOI
10.1007/s00125-014-3343-4

Glycerol-3-phosphate acyltransferase (GPAT)-1, but not GPAT4, incorporates newly synthesized fatty acids into triacylglycerol and diminishes fatty acid oxidation.

Four glycerol-3-phosphate acyltransferase (GPAT) isoforms, each encoded by a separate gene, catalyze the initial step in glycerolipid synthesis; in liver, the major isoforms are GPAT1 and GPAT4. To determine whether each of these hepatic isoforms performs a unique function in the metabolism of fatty acid, we measured the incorporation of de novo synthesized fatty acid or exogenous fatty acid into complex lipids in primary mouse hepatocytes from control, Gpat1(-/-), and Gpat4(-/-) mice. Although hepatocytes from each genotype incorporated a similar amount of exogenous fatty acid into triacylglycerol (TAG), only control and Gpat4(-/-) hepatocytes were able to incorporate de novo synthesized fatty acid into TAG. When compared with controls, Gpat1(-/-) hepatocytes oxidized twice as much exogenous fatty acid. To confirm these findings and to assess hepatic β-oxidation metabolites, we measured acylcarnitines in liver from mice after a 24-h fast and after a 24-h fast followed by 48 h of refeeding with a high sucrose diet to promote lipogenesis. Confirming the in vitro findings, the hepatic content of long-chain acylcarnitine in fasted Gpat1(-/-) mice was 3-fold higher than in controls. When compared with control and Gpat4(-/-) mice, after the fasting-refeeding protocol, Gpat1(-/-) hepatic TAG was depleted, and long-chain acylcarnitine content was 3.5-fold higher. Taken together, these data demonstrate that GPAT1, but not GPAT4, is required to incorporate de novo synthesized fatty acids into TAG and to divert them away from oxidation.

Authors
Wendel, AA; Cooper, DE; Ilkayeva, OR; Muoio, DM; Coleman, RA
MLA Citation
Wendel, AA, Cooper, DE, Ilkayeva, OR, Muoio, DM, and Coleman, RA. "Glycerol-3-phosphate acyltransferase (GPAT)-1, but not GPAT4, incorporates newly synthesized fatty acids into triacylglycerol and diminishes fatty acid oxidation." J Biol Chem 288.38 (September 20, 2013): 27299-27306.
PMID
23908354
Source
pubmed
Published In
The Journal of biological chemistry
Volume
288
Issue
38
Publish Date
2013
Start Page
27299
End Page
27306
DOI
10.1074/jbc.M113.485219

Increased Muscle Mitochondrial Mass in MCK-PGC1 alpha Transgenic Mice Alters Metabolic Responses to Diet and Exercise Intervention But Does Not Improve Clinically Relevant Outcomes

Authors
Wong, KE; Koves, TR; Stevens, RD; Ikayeva, O; Slentz, D; Muoio, DM
MLA Citation
Wong, KE, Koves, TR, Stevens, RD, Ikayeva, O, Slentz, D, and Muoio, DM. "Increased Muscle Mitochondrial Mass in MCK-PGC1 alpha Transgenic Mice Alters Metabolic Responses to Diet and Exercise Intervention But Does Not Improve Clinically Relevant Outcomes." DIABETES 62 (July 2013): A15-A15.
Source
wos-lite
Published In
Diabetes
Volume
62
Publish Date
2013
Start Page
A15
End Page
A15

SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase.

Lipid metabolism is tightly controlled by the nutritional state of the organism. Nutrient-rich conditions increase lipogenesis, whereas nutrient deprivation promotes fat oxidation. In this study, we identify the mitochondrial sirtuin, SIRT4, as a regulator of lipid homeostasis. SIRT4 is active in nutrient-replete conditions to repress fatty acid oxidation while promoting lipid anabolism. SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD), an enzyme that produces acetyl CoA from malonyl CoA. Malonyl CoA provides the carbon skeleton for lipogenesis and also inhibits fat oxidation. Mice lacking SIRT4 display elevated MCD activity and decreased malonyl CoA in skeletal muscle and white adipose tissue. Consequently, SIRT4 KO mice display deregulated lipid metabolism, leading to increased exercise tolerance and protection against diet-induced obesity. In sum, this work elucidates SIRT4 as an important regulator of lipid homeostasis, identifies MCD as a SIRT4 target, and deepens our understanding of the malonyl CoA regulatory axis.

Authors
Laurent, G; German, NJ; Saha, AK; de Boer, VCJ; Davies, M; Koves, TR; Dephoure, N; Fischer, F; Boanca, G; Vaitheesvaran, B; Lovitch, SB; Sharpe, AH; Kurland, IJ; Steegborn, C; Gygi, SP; Muoio, DM; Ruderman, NB; Haigis, MC
MLA Citation
Laurent, G, German, NJ, Saha, AK, de Boer, VCJ, Davies, M, Koves, TR, Dephoure, N, Fischer, F, Boanca, G, Vaitheesvaran, B, Lovitch, SB, Sharpe, AH, Kurland, IJ, Steegborn, C, Gygi, SP, Muoio, DM, Ruderman, NB, and Haigis, MC. "SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase." Mol Cell 50.5 (June 6, 2013): 686-698.
PMID
23746352
Source
pubmed
Published In
Molecular Cell
Volume
50
Issue
5
Publish Date
2013
Start Page
686
End Page
698
DOI
10.1016/j.molcel.2013.05.012

A lipidomics analysis of the relationship between dietary fatty acid composition and insulin sensitivity in young adults.

Relative to diets enriched in palmitic acid (PA), diets rich in oleic acid (OA) are associated with reduced risk of type 2 diabetes. To gain insight into mechanisms underlying these observations, we applied comprehensive lipidomic profiling to specimens collected from healthy adults enrolled in a randomized, crossover trial comparing a high-PA diet to a low-PA/high-OA (HOA) diet. Effects on insulin sensitivity (SI) and disposition index (DI) were assessed by intravenous glucose tolerance testing. In women, but not men, SI and DI were higher during HOA. The effect of HOA on SI correlated positively with physical fitness upon enrollment. Principal components analysis of either fasted or fed-state metabolites identified one factor affected by diet and heavily weighted by the PA/OA ratio of serum and muscle lipids. In women, this factor correlated inversely with SI in the fasted and fed states. Medium-chain acylcarnitines emerged as strong negative correlates of SI, and the HOA diet was accompanied by lower serum and muscle ceramide concentrations and reductions in molecular biomarkers of inflammatory and oxidative stress. This study provides evidence that the dietary PA/OA ratio impacts diabetes risk in women.

Authors
Kien, CL; Bunn, JY; Poynter, ME; Stevens, R; Bain, J; Ikayeva, O; Fukagawa, NK; Champagne, CM; Crain, KI; Koves, TR; Muoio, DM
MLA Citation
Kien, CL, Bunn, JY, Poynter, ME, Stevens, R, Bain, J, Ikayeva, O, Fukagawa, NK, Champagne, CM, Crain, KI, Koves, TR, and Muoio, DM. "A lipidomics analysis of the relationship between dietary fatty acid composition and insulin sensitivity in young adults." Diabetes 62.4 (April 2013): 1054-1063.
PMID
23238293
Source
pubmed
Published In
Diabetes
Volume
62
Issue
4
Publish Date
2013
Start Page
1054
End Page
1063
DOI
10.2337/db12-0363

Substituting dietary monounsaturated fat for saturated fat is associated with increased daily physical activity and resting energy expenditure and with changes in mood.

BACKGROUND: The Western diet increases risk of metabolic disease. OBJECTIVE: We determined whether lowering the ratio of saturated fatty acids to monounsaturated fatty acids in the Western diet would affect physical activity and energy expenditure. DESIGN: With the use of a balanced design, 2 cohorts of 18 and 14 young adults were enrolled in separate randomized, double-masked, crossover trials that compared a 3-wk high-palmitic acid diet (HPA; similar to the Western diet fat composition) to a low-palmitic acid and high-oleic acid diet (HOA; similar to the Mediterranean diet fat composition). All foods were provided by the investigators, and the palmitic acid (PA):oleic acid (OA) ratio was manipulated by adding different oil blends to the same foods. In both cohorts, we assessed physical activity (monitored continuously by using accelerometry) and resting energy expenditure (REE). To gain insight into a possible mood disturbance that might explain changes in physical activity, the Profile of Mood States (POMS) was administered in cohort 2. RESULTS: Physical activity was higher during the HOA than during the HPA in 15 of 17 subjects in cohort 1 (P = 0.008) (mean: 12% higher; P = 0.003) and in 12 of 12 subjects in the second, confirmatory cohort (P = 0.005) (mean: 15% higher; P = 0.003). When the HOA was compared with the HPA, REE measured during the fed state was 3% higher for cohort 1 (P < 0.01), and REE was 4.5% higher in the fasted state for cohort 2 (P = 0.04). POMS testing showed that the anger-hostility score was significantly higher during the HPA (P = 0.007). CONCLUSIONS: The replacement of dietary PA with OA was associated with increased physical activity and REE and less anger. Besides presumed effects on mitochondrial function (increased REE), the dietary PA:OA ratio appears to affect behavior. The second cohort was derived from a study that was registered at clinicaltrials.gov as R01DK082803.

Authors
Kien, CL; Bunn, JY; Tompkins, CL; Dumas, JA; Crain, KI; Ebenstein, DB; Koves, TR; Muoio, DM
MLA Citation
Kien, CL, Bunn, JY, Tompkins, CL, Dumas, JA, Crain, KI, Ebenstein, DB, Koves, TR, and Muoio, DM. "Substituting dietary monounsaturated fat for saturated fat is associated with increased daily physical activity and resting energy expenditure and with changes in mood." Am J Clin Nutr 97.4 (April 2013): 689-697.
PMID
23446891
Source
pubmed
Published In
American Journal of Clinical Nutrition
Volume
97
Issue
4
Publish Date
2013
Start Page
689
End Page
697
DOI
10.3945/ajcn.112.051730

Substituting dietary monounsaturated fat for saturated fat is associated with increased daily physical activity and resting energy expenditure and with changes in mood

Authors
Kien, CL; Bunn, JY; Tompkins, CL; Dumas, JA; Crain, KI; Ebenstein, DB; Koves, TR; Muoio, DM
MLA Citation
Kien, CL, Bunn, JY, Tompkins, CL, Dumas, JA, Crain, KI, Ebenstein, DB, Koves, TR, and Muoio, DM. "Substituting dietary monounsaturated fat for saturated fat is associated with increased daily physical activity and resting energy expenditure and with changes in mood." April 2013.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
27
Publish Date
2013

Highlights of the 2012 Research Workshop: Using nutrigenomics and metabolomics in clinical nutrition research.

The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Research Workshop, "Using Nutrigenomics and Metabolomics in Clinical Nutrition Research," was held on January 21, 2012, in Orlando, Florida. The conference brought together experts in human nutrition who use nutrigenomic and metabolomic methods to better understand metabolic individuality and nutrition effects on health. We are beginning to understand how genetic variation and epigenetic events alter requirements for and responses to foods in our diet (the field of nutrigenetics/nutrigenomics and epigenetics). At the same time, methods for profiling almost all of the products of metabolism in plasma, urine, and tissues (metabolomics) are being refined. The relationships between diet and nutrigenomic-metabolomic profiles, as well as between these profiles and health, are being elucidated, and this will dramatically alter clinical practice in nutrition.

Authors
Zeisel, SH; Waterland, RA; Ordovás, JM; Muoio, DM; Jia, W; Fodor, A
MLA Citation
Zeisel, SH, Waterland, RA, Ordovás, JM, Muoio, DM, Jia, W, and Fodor, A. "Highlights of the 2012 Research Workshop: Using nutrigenomics and metabolomics in clinical nutrition research." JPEN J Parenter Enteral Nutr 37.2 (March 2013): 190-200.
PMID
23042849
Source
pubmed
Published In
Journal of Parenteral and Enteral Nutrition
Volume
37
Issue
2
Publish Date
2013
Start Page
190
End Page
200
DOI
10.1177/0148607112462401

PPARγ coactivator-1α contributes to exercise-induced regulation of intramuscular lipid droplet programming in mice and humans.

Intramuscular accumulation of triacylglycerol, in the form of lipid droplets (LD), has gained widespread attention as a hallmark of metabolic disease and insulin resistance. Paradoxically, LDs also amass in muscles of highly trained endurance athletes who are exquisitely insulin sensitive. Understanding the molecular mechanisms that mediate the expansion and appropriate metabolic control of LDs in the context of habitual physical activity could lead to new therapeutic opportunities. Herein, we show that acute exercise elicits robust upregulation of a broad program of genes involved in regulating LD assembly, morphology, localization, and mobilization. Prominent among these was perilipin-5, a scaffolding protein that affects the spatial and metabolic interactions between LD and their surrounding mitochondrial reticulum. Studies in transgenic mice and primary human skeletal myocytes established a key role for the exercise-responsive transcriptional coactivator PGC-1α in coordinating intramuscular LD programming with mitochondrial remodeling. Moreover, translational studies comparing physically active versus inactive humans identified a remarkably strong association between expression of intramuscular LD genes and enhanced insulin action in exercise-trained subjects. These results reveal an intimate molecular connection between intramuscular LD biology and mitochondrial metabolism that could prove relevant to the etiology and treatment of insulin resistance and other disorders of lipid imbalance.

Authors
Koves, TR; Sparks, LM; Kovalik, JP; Mosedale, M; Arumugam, R; DeBalsi, KL; Everingham, K; Thorne, L; Phielix, E; Meex, RC; Kien, CL; Hesselink, MKC; Schrauwen, P; Muoio, DM
MLA Citation
Koves, TR, Sparks, LM, Kovalik, JP, Mosedale, M, Arumugam, R, DeBalsi, KL, Everingham, K, Thorne, L, Phielix, E, Meex, RC, Kien, CL, Hesselink, MKC, Schrauwen, P, and Muoio, DM. "PPARγ coactivator-1α contributes to exercise-induced regulation of intramuscular lipid droplet programming in mice and humans." J Lipid Res 54.2 (February 2013): 522-534.
PMID
23175776
Source
pubmed
Published In
Journal of lipid research
Volume
54
Issue
2
Publish Date
2013
Start Page
522
End Page
534
DOI
10.1194/jlr.P028910

Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice.

Disruptions of ovarian function in women are associated with increased risk of metabolic disease due to dysregulation of peripheral glucose homeostasis in skeletal muscle. Our previous evidence suggests that alterations in skeletal muscle lipid metabolism coupled with altered mitochondrial function may also develop. The objective of this study was to use an integrative metabolic approach to identify potential areas of dysfunction that develop in skeletal muscle from ovariectomized (OVX) female mice compared with age-matched ovary-intact adult female mice (sham). The OVX mice exhibited significant increases in body weight, visceral, and inguinal fat mass compared with sham mice. OVX mice also had significant increases in skeletal muscle intramyocellular lipids (IMCL) compared with the sham animals, which corresponded to significant increases in the protein content of the fatty acid transporters CD36/FAT and FABPpm. A targeted metabolic profiling approach identified significantly lower levels of specific acyl carnitine species and various amino acids in skeletal muscle from OVX mice compared with the sham animals, suggesting a potential dysfunction in lipid and amino acid metabolism, respectively. Basal and maximal mitochondrial oxygen consumption rates were significantly impaired in skeletal muscle fibers from OVX mice compared with sham animals. Collectively, these data indicate that loss of ovarian function results in increased IMCL storage that is coupled with alterations in mitochondrial function and changes in the skeletal muscle metabolic profile.

Authors
Jackson, KC; Wohlers, LM; Lovering, RM; Schuh, RA; Maher, AC; Bonen, A; Koves, TR; Ilkayeva, O; Thomson, DM; Muoio, DM; Spangenburg, EE
MLA Citation
Jackson, KC, Wohlers, LM, Lovering, RM, Schuh, RA, Maher, AC, Bonen, A, Koves, TR, Ilkayeva, O, Thomson, DM, Muoio, DM, and Spangenburg, EE. "Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice." Am J Physiol Regul Integr Comp Physiol 304.3 (February 2013): R206-R217.
PMID
23193112
Source
pubmed
Published In
American journal of physiology. Regulatory, integrative and comparative physiology
Volume
304
Issue
3
Publish Date
2013
Start Page
R206
End Page
R217
DOI
10.1152/ajpregu.00428.2012

Genome-wide chromatin state transitions associated with developmental and environmental cues.

Differences in chromatin organization are key to the multiplicity of cell states that arise from a single genetic background, yet the landscapes of in vivo tissues remain largely uncharted. Here, we mapped chromatin genome-wide in a large and diverse collection of human tissues and stem cells. The maps yield unprecedented annotations of functional genomic elements and their regulation across developmental stages, lineages, and cellular environments. They also reveal global features of the epigenome, related to nuclear architecture, that also vary across cellular phenotypes. Specifically, developmental specification is accompanied by progressive chromatin restriction as the default state transitions from dynamic remodeling to generalized compaction. Exposure to serum in vitro triggers a distinct transition that involves de novo establishment of domains with features of constitutive heterochromatin. We describe how these global chromatin state transitions relate to chromosome and nuclear architecture, and discuss their implications for lineage fidelity, cellular senescence, and reprogramming.

Authors
Zhu, J; Adli, M; Zou, JY; Verstappen, G; Coyne, M; Zhang, X; Durham, T; Miri, M; Deshpande, V; De Jager, PL; Bennett, DA; Houmard, JA; Muoio, DM; Onder, TT; Camahort, R; Cowan, CA; Meissner, A; Epstein, CB; Shoresh, N; Bernstein, BE
MLA Citation
Zhu, J, Adli, M, Zou, JY, Verstappen, G, Coyne, M, Zhang, X, Durham, T, Miri, M, Deshpande, V, De Jager, PL, Bennett, DA, Houmard, JA, Muoio, DM, Onder, TT, Camahort, R, Cowan, CA, Meissner, A, Epstein, CB, Shoresh, N, and Bernstein, BE. "Genome-wide chromatin state transitions associated with developmental and environmental cues." Cell 152.3 (January 31, 2013): 642-654.
PMID
23333102
Source
pubmed
Published In
Cell
Volume
152
Issue
3
Publish Date
2013
Start Page
642
End Page
654
DOI
10.1016/j.cell.2012.12.033

Erratum: Substituting dietary monounsaturated fat for saturated fat is associated with increased daily physical activity and resting energy expenditure and with changes in mood (American Journal of Clinical Nutrition (2013) 97 (689-697))

Authors
Kien, CL; Bunn, JY; Tompkins, CL; Dumas, JA; Crain, KI; Ebenstein, DB; Koves, TR; Muoio, DM
MLA Citation
Kien, CL, Bunn, JY, Tompkins, CL, Dumas, JA, Crain, KI, Ebenstein, DB, Koves, TR, and Muoio, DM. "Erratum: Substituting dietary monounsaturated fat for saturated fat is associated with increased daily physical activity and resting energy expenditure and with changes in mood (American Journal of Clinical Nutrition (2013) 97 (689-697))." American Journal of Clinical Nutrition 98.2 (2013): 511--.
Source
scival
Published In
American Journal of Clinical Nutrition
Volume
98
Issue
2
Publish Date
2013
Start Page
511-
DOI
10.3945/ajcn.113.066282

Identification of a novel malonyl-CoA IC(50) for CPT-I: implications for predicting in vivo fatty acid oxidation rates.

Published values regarding the sensitivity (IC(50)) of CPT-I (carnitine palmitoyltransferase I) to M-CoA (malonyl-CoA) inhibition in isolated mitochondria are inconsistent with predicted in vivo rates of fatty acid oxidation. Therefore we have re-examined M-CoA inhibition kinetics under various P-CoA (palmitoyl-CoA) concentrations in both isolated mitochondria and PMFs (permeabilized muscle fibres). PMFs have an 18-fold higher IC(50) (0.61 compared with 0.034 μM) in the presence of 25 μM P-CoA and a 13-fold higher IC(50) (6.3 compared with 0.49 μM) in the presence of 150 μM P-CoA compared with isolated mitochondria. M-CoA inhibition kinetics determined in PMFs predicts that CPT-I activity is inhibited by 33% in resting muscle compared with >95% in isolated mitochondria. Additionally, the ability of M-CoA to inhibit CPT-I appears to be dependent on P-CoA concentration, as the relative inhibitory capacity of M-CoA is decreased with increasing P-CoA concentrations. Altogether, the use of PMFs appears to provide an M-CoA IC(50) that better reflects the predicted in vivo rates of fatty acid oxidation. These findings also demonstrate that the ratio of [P-CoA]/[M-CoA] is critical for regulating CPT-I activity and may partially rectify the in vivo disconnect between M-CoA content and CPT-I flux within the context of exercise and Type 2 diabetes.

Authors
Smith, BK; Perry, CGR; Koves, TR; Wright, DC; Smith, JC; Neufer, PD; Muoio, DM; Holloway, GP
MLA Citation
Smith, BK, Perry, CGR, Koves, TR, Wright, DC, Smith, JC, Neufer, PD, Muoio, DM, and Holloway, GP. "Identification of a novel malonyl-CoA IC(50) for CPT-I: implications for predicting in vivo fatty acid oxidation rates." Biochem J 448.1 (November 15, 2012): 13-20.
PMID
22928974
Source
pubmed
Published In
The Biochemical journal
Volume
448
Issue
1
Publish Date
2012
Start Page
13
End Page
20
DOI
10.1042/BJ20121110

Revisiting the connection between intramyocellular lipids and insulin resistance: A long and winding road

In the mid-1990s, researchers began to re-examine type 2 diabetes from a more 'lipocentric' perspective; giving strong consideration to the idea that systemic lipid imbalances give rise to glucose dysregulation, rather than vice versa. At the forefront of this paradigm shift was a report by Krssak and colleagues (Diabetologia 1999; 42:113-116) showing that intramyocellular lipid content, measured via the (then) novel application of proton nuclear magnetic resonance spectroscopy, served as a robust indicator of muscle insulin sensitivity in healthy individuals. A subsequent wave of investigations produced compelling correlative evidence linking ectopic lipid deposition within skeletal myocytes to the development of obesity-associated insulin resistance. But this relationship has proven much more complex than originally imagined, and scientists today are still left wondering if and how the intramyocellular accumulation of lipid droplets has a direct bearing on insulin action. Originally viewed as a simple storage depot, the lipid droplet is now recognised as an essential and sophisticated organelle that actively participates in numerous cellular processes. This edition of 'Then and now' revisits the connection between intramuscular lipids and insulin resistance and looks to future research aimed at understanding the dynamic interplay between lipid droplet biology and metabolic health. © 2012 Springer-Verlag.

Authors
Muoio, DM
MLA Citation
Muoio, DM. "Revisiting the connection between intramyocellular lipids and insulin resistance: A long and winding road." Diabetologia 55.10 (October 1, 2012): 2521-2554.
Source
scopus
Published In
Diabetologia
Volume
55
Issue
10
Publish Date
2012
Start Page
2521
End Page
2554
DOI
10.1007/s00125-012-2597-y

Revisiting the connection between intramyocellular lipids and insulin resistance: a long and winding road.

In the mid-1990s, researchers began to re-examine type 2 diabetes from a more 'lipocentric' perspective; giving strong consideration to the idea that systemic lipid imbalances give rise to glucose dysregulation, rather than vice versa. At the forefront of this paradigm shift was a report by Krssak and colleagues (Diabetologia 1999; 42:113-116) showing that intramyocellular lipid content, measured via the (then) novel application of proton nuclear magnetic resonance spectroscopy, served as a robust indicator of muscle insulin sensitivity in healthy individuals. A subsequent wave of investigations produced compelling correlative evidence linking ectopic lipid deposition within skeletal myocytes to the development of obesity-associated insulin resistance. But this relationship has proven much more complex than originally imagined, and scientists today are still left wondering if and how the intramyocellular accumulation of lipid droplets has a direct bearing on insulin action. Originally viewed as a simple storage depot, the lipid droplet is now recognised as an essential and sophisticated organelle that actively participates in numerous cellular processes. This edition of 'Then and now' revisits the connection between intramuscular lipids and insulin resistance and looks to future research aimed at understanding the dynamic interplay between lipid droplet biology and metabolic health.

Authors
Muoio, DM
MLA Citation
Muoio, DM. "Revisiting the connection between intramyocellular lipids and insulin resistance: a long and winding road." Diabetologia 55.10 (October 2012): 2551-2554.
PMID
22660796
Source
pubmed
Published In
Diabetologia
Volume
55
Issue
10
Publish Date
2012
Start Page
2551
End Page
2554
DOI
10.1007/s00125-012-2597-y

Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility.

The concept of "metabolic inflexibility" was first introduced to describe the failure of insulin-resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing recognition as a core component of the metabolic syndrome, but the underlying mechanisms have remained elusive. Here, we identify an essential role for the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT), in regulating substrate switching and glucose tolerance. By converting acetyl-CoA to its membrane permeant acetylcarnitine ester, CrAT regulates mitochondrial and intracellular carbon trafficking. Studies in muscle-specific Crat knockout mice, primary human skeletal myocytes, and human subjects undergoing L-carnitine supplementation support a model wherein CrAT combats nutrient stress, promotes metabolic flexibility, and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase. These findings offer therapeutically relevant insights into the molecular basis of metabolic inflexibility.

Authors
Muoio, DM; Noland, RC; Kovalik, J-P; Seiler, SE; Davies, MN; DeBalsi, KL; Ilkayeva, OR; Stevens, RD; Kheterpal, I; Zhang, J; Covington, JD; Bajpeyi, S; Ravussin, E; Kraus, W; Koves, TR; Mynatt, RL
MLA Citation
Muoio, DM, Noland, RC, Kovalik, J-P, Seiler, SE, Davies, MN, DeBalsi, KL, Ilkayeva, OR, Stevens, RD, Kheterpal, I, Zhang, J, Covington, JD, Bajpeyi, S, Ravussin, E, Kraus, W, Koves, TR, and Mynatt, RL. "Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility." Cell Metab 15.5 (May 2, 2012): 764-777.
PMID
22560225
Source
pubmed
Published In
Cell Metabolism
Volume
15
Issue
5
Publish Date
2012
Start Page
764
End Page
777
DOI
10.1016/j.cmet.2012.04.005

Lipid-induced mitochondrial stress and insulin action in muscle.

The interplay between mitochondrial energetics, lipid balance, and muscle insulin sensitivity has remained a topic of intense interest and debate for decades. One popular view suggests that increased oxidative capacity benefits metabolic wellness, based on the premise that it is healthier to burn fat than glucose. Attempts to test this hypothesis using genetically modified mouse models have produced contradictory results and instead link muscle insulin resistance to excessive fat oxidation, acylcarnitine production, and increased mitochondrial H(2)O(2)-emitting potential. Here, we consider emerging evidence that insulin action in muscle is driven principally by mitochondrial load and redox signaling rather than oxidative capacity.

Authors
Muoio, DM; Neufer, PD
MLA Citation
Muoio, DM, and Neufer, PD. "Lipid-induced mitochondrial stress and insulin action in muscle." Cell Metab 15.5 (May 2, 2012): 595-605.
PMID
22560212
Source
pubmed
Published In
Cell Metabolism
Volume
15
Issue
5
Publish Date
2012
Start Page
595
End Page
605
DOI
10.1016/j.cmet.2012.04.010

Caloric restriction, aerobic exercise or a combination improves metabolic profiles following diet-induced obesity

Authors
Glynn, EL; An, J; Wang, L-P; Ilkayeva, OR; Stevens, RD; Bain, JR; Muehlbauer, MJ; Koves, TR; Summers, SA; Muoio, DM; Newgard, CB
MLA Citation
Glynn, EL, An, J, Wang, L-P, Ilkayeva, OR, Stevens, RD, Bain, JR, Muehlbauer, MJ, Koves, TR, Summers, SA, Muoio, DM, and Newgard, CB. "Caloric restriction, aerobic exercise or a combination improves metabolic profiles following diet-induced obesity." April 2012.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
26
Publish Date
2012

Distinct roles of specific fatty acids in cellular processes: implications for interpreting and reporting experiments.

Plasma contains a variety of long-chain fatty acids (FAs), such that about 35% are saturated and 65% are unsaturated. There are countless examples that show how different FAs impart specific and unique effects, or even opposing actions, on cellular function. Despite these differing effects, palmitate (C16:0) is regularly used to represent "FAs" in cell based experiments. Although palmitate can be useful to induce and study stress effects in cultured cells, these effects in isolation are not physiologically relevant to dietary manipulations, obesity, or the consequences of physiological concentrations of FAs. Hence, authors should avoid conclusions that generalize about "FAs" or "saturated FAs" or "high-fat diet" effects if only a single FA was used in the reported experiments.

Authors
Watt, MJ; Hoy, AJ; Muoio, DM; Coleman, RA
MLA Citation
Watt, MJ, Hoy, AJ, Muoio, DM, and Coleman, RA. "Distinct roles of specific fatty acids in cellular processes: implications for interpreting and reporting experiments." Am J Physiol Endocrinol Metab 302.1 (January 1, 2012): E1-E3.
PMID
22180647
Source
pubmed
Published In
American journal of physiology. Endocrinology and metabolism
Volume
302
Issue
1
Publish Date
2012
Start Page
E1
End Page
E3
DOI
10.1152/ajpendo.00418.2011

Revisiting the connection between intramyocellular lipids and insulin resistance: a long and winding road.

In the mid-1990s, researchers began to re-examine type 2 diabetes from a more 'lipocentric' perspective; giving strong consideration to the idea that systemic lipid imbalances give rise to glucose dysregulation, rather than vice versa. At the forefront of this paradigm shift was a report by Krssak and colleagues (Diabetologia 1999; 42:113-116) showing that intramyocellular lipid content, measured via the (then) novel application of proton nuclear magnetic resonance spectroscopy, served as a robust indicator of muscle insulin sensitivity in healthy individuals. A subsequent wave of investigations produced compelling correlative evidence linking ectopic lipid deposition within skeletal myocytes to the development of obesity-associated insulin resistance. But this relationship has proven much more complex than originally imagined, and scientists today are still left wondering if and how the intramyocellular accumulation of lipid droplets has a direct bearing on insulin action. Originally viewed as a simple storage depot, the lipid droplet is now recognised as an essential and sophisticated organelle that actively participates in numerous cellular processes. This edition of 'Then and now' revisits the connection between intramuscular lipids and insulin resistance and looks to future research aimed at understanding the dynamic interplay between lipid droplet biology and metabolic health.

Authors
Muoio, DM
MLA Citation
Muoio, DM. "Revisiting the connection between intramyocellular lipids and insulin resistance: a long and winding road." Diabetologia 55.10 (2012): 2551-2554.
Source
scival
Published In
Diabetologia
Volume
55
Issue
10
Publish Date
2012
Start Page
2551
End Page
2554
DOI
10.1007/s00125-012-2597-y

Re-patterning of skeletal muscle energy metabolism by fat storage-inducing transmembrane protein 2.

Triacylglyceride stored in cytosolic lipid droplets (LDs) constitutes a major energy reservoir in most eukaryotes. The regulated turnover of triacylglyceride in LDs provides fatty acids for mitochondrial β-oxidation and ATP generation in physiological states of high demand for energy. The mechanisms for the formation of LDs in conditions of energy excess are not entirely understood. Fat storage-inducing transmembrane protein 2 (FIT2/FITM2) is the anciently conserved member of the fat storage-inducing transmembrane family of proteins implicated to be important in the formation of LDs, but its role in energy metabolism has not been tested. Here, we report that expression of FIT2 in mouse skeletal muscle had profound effects on muscle energy metabolism. Mice with skeletal muscle-specific overexpression of FIT2 (CKF2) had significantly increased intramyocellular triacylglyceride and complete protection from high fat diet-induced weight gain due to increased energy expenditure. Mass spectrometry-based metabolite profiling suggested that CKF2 skeletal muscle had increased oxidation of branched chain amino acids but decreased oxidation of fatty acids. Glucose was primarily utilized in CKF2 muscle for synthesis of the glycerol backbone of triacylglyceride and not for glycogen production. CKF2 muscle was ATP-deficient and had activated AMP kinase. Together, these studies indicate that FIT2 expression in skeletal muscle plays an unexpected function in regulating muscle energy metabolism and indicates an important role for lipid droplet formation in this process.

Authors
Miranda, DA; Koves, TR; Gross, DA; Chadt, A; Al-Hasani, H; Cline, GW; Schwartz, GJ; Muoio, DM; Silver, DL
MLA Citation
Miranda, DA, Koves, TR, Gross, DA, Chadt, A, Al-Hasani, H, Cline, GW, Schwartz, GJ, Muoio, DM, and Silver, DL. "Re-patterning of skeletal muscle energy metabolism by fat storage-inducing transmembrane protein 2." J Biol Chem 286.49 (December 9, 2011): 42188-42199.
PMID
22002063
Source
pubmed
Published In
The Journal of biological chemistry
Volume
286
Issue
49
Publish Date
2011
Start Page
42188
End Page
42199
DOI
10.1074/jbc.M111.297127

Metabolic remodeling of human skeletal myocytes by cocultured adipocytes depends on the lipolytic state of the system.

OBJECTIVE: Adipocyte infiltration of the musculoskeletal system is well recognized as a hallmark of aging, obesity, and type 2 diabetes. Intermuscular adipocytes might serve as a benign storage site for surplus lipid or play a role in disrupting energy homeostasis as a result of dysregulated lipolysis or secretion of proinflammatory cytokines. This investigation sought to understand the net impact of local adipocytes on skeletal myocyte metabolism. RESEARCH DESIGN AND METHODS: Interactions between these two tissues were modeled using a coculture system composed of primary human adipocytes and human skeletal myotubes derived from lean or obese donors. Metabolic analysis of myocytes was performed after coculture with lipolytically silent or activated adipocytes and included transcript and metabolite profiling along with assessment of substrate selection and insulin action. RESULTS: Cocultured adipocytes increased myotube mRNA expression of genes involved in oxidative metabolism, regardless of the donor and degree of lipolytic activity. Adipocytes in the basal state sequestered free fatty acids, thereby forcing neighboring myotubes to rely more heavily on glucose fuel. Under this condition, insulin action was enhanced in myotubes from lean but not obese donors. In contrast, when exposed to lipolytically active adipocytes, cocultured myotubes shifted substrate use in favor of fatty acids, which was accompanied by intracellular accumulation of triacylglycerol and even-chain acylcarnitines, decreased glucose oxidation, and modest attenuation of insulin signaling. CONCLUSIONS: The effects of cocultured adipocytes on myocyte substrate selection and insulin action depended on the metabolic state of the system. These findings are relevant to understanding the metabolic consequences of intermuscular adipogenesis.

Authors
Kovalik, J-P; Slentz, D; Stevens, RD; Kraus, WE; Houmard, JA; Nicoll, JB; Lea-Currie, YR; Everingham, K; Kien, CL; Buehrer, BM; Muoio, DM
MLA Citation
Kovalik, J-P, Slentz, D, Stevens, RD, Kraus, WE, Houmard, JA, Nicoll, JB, Lea-Currie, YR, Everingham, K, Kien, CL, Buehrer, BM, and Muoio, DM. "Metabolic remodeling of human skeletal myocytes by cocultured adipocytes depends on the lipolytic state of the system." Diabetes 60.7 (July 2011): 1882-1893.
PMID
21602515
Source
pubmed
Published In
Diabetes
Volume
60
Issue
7
Publish Date
2011
Start Page
1882
End Page
1893
DOI
10.2337/db10-0427

Mouse cardiac acyl coenzyme a synthetase 1 deficiency impairs Fatty Acid oxidation and induces cardiac hypertrophy.

Long-chain acyl coenzyme A (acyl-CoA) synthetase isoform 1 (ACSL1) catalyzes the synthesis of acyl-CoA from long-chain fatty acids and contributes the majority of cardiac long-chain acyl-CoA synthetase activity. To understand its functional role in the heart, we studied mice lacking ACSL1 globally (Acsl1(T-/-)) and mice lacking ACSL1 in heart ventricles (Acsl1(H-/-)) at different times. Compared to littermate controls, heart ventricular ACSL activity in Acsl1(T-/-) mice was reduced more than 90%, acyl-CoA content was 65% lower, and long-chain acyl-carnitine content was 80 to 90% lower. The rate of [(14)C]palmitate oxidation in both heart homogenate and mitochondria was 90% lower than in the controls, and the maximal rates of [(14)C]pyruvate and [(14)C]glucose oxidation were each 20% higher. The mitochondrial area was 54% greater than in the controls with twice as much mitochondrial DNA, and the mRNA abundance of Pgc1α and Errα increased by 100% and 41%, respectively. Compared to the controls, Acsl1(T-/-) and Acsl1(H-/-) hearts were hypertrophied, and the phosphorylation of S6 kinase, a target of mammalian target of rapamycin (mTOR) kinase, increased 5-fold. Our data suggest that ACSL1 is required to synthesize the acyl-CoAs that are oxidized by the heart, and that without ACSL1, diminished fatty acid (FA) oxidation and compensatory catabolism of glucose and amino acids lead to mTOR activation and cardiac hypertrophy without lipid accumulation or immediate cardiac dysfunction.

Authors
Ellis, JM; Mentock, SM; Depetrillo, MA; Koves, TR; Sen, S; Watkins, SM; Muoio, DM; Cline, GW; Taegtmeyer, H; Shulman, GI; Willis, MS; Coleman, RA
MLA Citation
Ellis, JM, Mentock, SM, Depetrillo, MA, Koves, TR, Sen, S, Watkins, SM, Muoio, DM, Cline, GW, Taegtmeyer, H, Shulman, GI, Willis, MS, and Coleman, RA. "Mouse cardiac acyl coenzyme a synthetase 1 deficiency impairs Fatty Acid oxidation and induces cardiac hypertrophy." Mol Cell Biol 31.6 (March 2011): 1252-1262.
PMID
21245374
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
31
Issue
6
Publish Date
2011
Start Page
1252
End Page
1262
DOI
10.1128/MCB.01085-10

A high-fat diet elicits differential responses in genes coordinating oxidative metabolism in skeletal muscle of lean and obese individuals.

CONTEXT: In lean individuals, increasing dietary lipid can elicit an increase in whole body lipid oxidation; however, with obesity the capacity to respond to changes in substrate availability appears to be compromised. OBJECTIVE: To determine whether the responses of genes regulating lipid oxidation in skeletal muscle differed between lean and insulin resistant obese humans upon exposure to a high-fat diet (HFD). DESIGN AND SETTING: A 5-d prospective study conducted in the research unit of an academic center. PARTICIPANTS: Healthy, lean (n = 12; body mass index = 22.1 ± 0.6 kg/m(2)), and obese (n=10; body mass index = 39.6 ± 1.7 kg/m(2)) males and females, between ages 18 and 30. INTERVENTION: Participants were studied before and after a 5-d HFD (65% fat). MAIN OUTCOME MEASURES: Skeletal muscle biopsies (vastus lateralis) were obtained in the fasted and fed states before and after the HFD and mRNA content for genes involved with lipid oxidation determined. Skeletal muscle acylcarnitine content was determined in the fed states before and after the HFD. RESULTS: Peroxisome proliferator activated receptor (PPAR) α mRNA content increased in lean, but not obese, subjects after a single high-fat meal. From Pre- to Post-HFD, mRNA content exhibited a body size × HFD interaction, where the lean individuals increased while the obese individuals decreased mRNA content for pyruvate dehydrogenase kinase 4, uncoupling protein 3, PPARα, and PPARγ coactivator-1α (P ≤ 0.05). In the obese subjects medium-chain acylcarnitine species tended to accumulate, whereas no change or a reduction was evident in the lean individuals. CONCLUSIONS: These findings indicate a differential response to a lipid stimulus in the skeletal muscle of lean and insulin resistant obese humans.

Authors
Boyle, KE; Canham, JP; Consitt, LA; Zheng, D; Koves, TR; Gavin, TP; Holbert, D; Neufer, PD; Ilkayeva, O; Muoio, DM; Houmard, JA
MLA Citation
Boyle, KE, Canham, JP, Consitt, LA, Zheng, D, Koves, TR, Gavin, TP, Holbert, D, Neufer, PD, Ilkayeva, O, Muoio, DM, and Houmard, JA. "A high-fat diet elicits differential responses in genes coordinating oxidative metabolism in skeletal muscle of lean and obese individuals." J Clin Endocrinol Metab 96.3 (March 2011): 775-781.
PMID
21190973
Source
pubmed
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
96
Issue
3
Publish Date
2011
Start Page
775
End Page
781
DOI
10.1210/jc.2010-2253

Short-term effects of dietary fatty acids on muscle lipid composition and serum acylcarnitine profile in human subjects.

In cultured cells, palmitic acid (PA) and oleic acid (OA) confer distinct metabolic effects, yet, unclear, is whether changes in dietary fat intake impact cellular fatty acid (FA) composition. We hypothesized that short-term increases in dietary PA or OA would result in corresponding changes in the FA composition of skeletal muscle diacylglycerol (DAG) and triacylglycerol (TAG) and/or the specific FA selected for β-oxidation. Healthy males (N = 12) and females (N = 12) ingested a low-PA diet for 7 days. After fasting measurements of the serum acylcarnitine (AC) profile, subjects were randomized to either high-PA (HI PA) or low-PA/high-OA (HI OA) diets. After 7 days, the fasting AC measurement was repeated and a muscle/fat biopsy obtained. FA composition of intramyocellular DAG and TAG and serum AC was measured. HI PA increased, whereas HI OA decreased, serum concentration of 16:0 AC (P < 0.001). HI OA increased 18:1 AC (P = 0.005). HI PA was associated with a higher PA/OA ratio in muscle DAG and TAG (DAG: 1.03 ± 0.24 vs. 0.46 ± 0.08, P = 0.04; TAG: 0.63 ± 0.07 vs. 0.41 ± 0.03, P = 0.01). The PA concentration in the adipose tissue DAG (µg/mg adipose tissue) was 0.17 ± 0.02 in those receiving the HI PA diet (n = 6), compared to 0.11 ± 0.02 in the HI OA group (n = 4) (P = 0.067). The relative PA concentration in muscle DAG and TAG and the serum palmitoylcarnitine concentration was higher in those fed the high-PA diet.

Authors
Kien, CL; Everingham, KI; D Stevens, R; Fukagawa, NK; Muoio, DM
MLA Citation
Kien, CL, Everingham, KI, D Stevens, R, Fukagawa, NK, and Muoio, DM. "Short-term effects of dietary fatty acids on muscle lipid composition and serum acylcarnitine profile in human subjects." Obesity (Silver Spring) 19.2 (February 2011): 305-311.
PMID
20559306
Source
pubmed
Published In
Obesity
Volume
19
Issue
2
Publish Date
2011
Start Page
305
End Page
311
DOI
10.1038/oby.2010.135

Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption.

OBJECTIVE: It has been proposed that skeletal muscle insulin resistance arises from the accumulation of intramyocellular lipid metabolites that impede insulin signaling, including diacylglycerol and ceramide. We determined the role of de novo ceramide synthesis in mediating muscle insulin resistance. RESEARCH DESIGN AND METHODS: Mice were subjected to 12 weeks of diet-induced obesity (DIO), and then treated for 4 weeks with myriocin, an inhibitor of serine palmitoyl transferase-1 (SPT1), the rate-limiting enzyme of de novo ceramide synthesis. RESULTS: After 12 weeks of DIO, C57BL/6 mice demonstrated a doubling in gastrocnemius ceramide content, which was completely reversed (141.5 ± 15.8 vs. 94.6 ± 10.2 nmol/g dry wt) via treatment with myriocin, whereas hepatic ceramide content was unaffected by DIO. Interestingly, myriocin treatment did not alter the DIO-associated increase in gastrocnemius diacyglycerol content, and the only correlation observed between lipid metabolite accumulation and glucose intolerance occurred with ceramide (R = 0.61). DIO mice treated with myriocin showed a complete reversal of glucose intolerance and insulin resistance which was associated with enhanced insulin-stimulated Akt and glycogen synthase kinase 3β phosphorylation. Furthermore, myriocin treatment also decreased intramyocellular ceramide content and prevented insulin resistance development in db/db mice. Finally, myriocin-treated DIO mice displayed enhanced oxygen consumption rates (3,041 ± 124 vs. 2,407 ± 124 ml/kg/h) versus their control counterparts. CONCLUSIONS: Our results demonstrate that the intramyocellular accumulation of ceramide correlates strongly with the development of insulin resistance, and suggests that inhibition of SPT1 is a potentially promising target for the treatment of insulin resistance.

Authors
Ussher, JR; Koves, TR; Cadete, VJJ; Zhang, L; Jaswal, JS; Swyrd, SJ; Lopaschuk, DG; Proctor, SD; Keung, W; Muoio, DM; Lopaschuk, GD
MLA Citation
Ussher, JR, Koves, TR, Cadete, VJJ, Zhang, L, Jaswal, JS, Swyrd, SJ, Lopaschuk, DG, Proctor, SD, Keung, W, Muoio, DM, and Lopaschuk, GD. "Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption." Diabetes 59.10 (October 2010): 2453-2464.
PMID
20522596
Source
pubmed
Published In
Diabetes
Volume
59
Issue
10
Publish Date
2010
Start Page
2453
End Page
2464
DOI
10.2337/db09-1293

Effects of High and Low Palmitic Acid Diets on Whole Body, Tissue, and Serum Lipids

Authors
Kien, CL; Bunn, JY; Champagne, CM; Everingham, KI; Koves, TR; Muoio, DM
MLA Citation
Kien, CL, Bunn, JY, Champagne, CM, Everingham, KI, Koves, TR, and Muoio, DM. "Effects of High and Low Palmitic Acid Diets on Whole Body, Tissue, and Serum Lipids." October 2010.
Source
wos-lite
Published In
Obesity (Silver Spring, Md.)
Volume
18
Publish Date
2010
Start Page
S103
End Page
S103

Effects of High and Low Palmitic Acid Diets on Fatty Acid Metabolism in Non-Obese Human Subjects

Authors
Kien, CL; Bunn, JY; Koves, T; Ilkayeva, O; Muoio, DM
MLA Citation
Kien, CL, Bunn, JY, Koves, T, Ilkayeva, O, and Muoio, DM. "Effects of High and Low Palmitic Acid Diets on Fatty Acid Metabolism in Non-Obese Human Subjects." October 2010.
Source
wos-lite
Published In
Obesity (Silver Spring, Md.)
Volume
18
Publish Date
2010
Start Page
S67
End Page
S67

Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA.

Although lactic acidosis is a prominent feature of solid tumors, we still have limited understanding of the mechanisms by which lactic acidosis influences metabolic phenotypes of cancer cells. We compared global transcriptional responses of breast cancer cells in response to three distinct tumor microenvironmental stresses: lactic acidosis, glucose deprivation, and hypoxia. We found that lactic acidosis and glucose deprivation trigger highly similar transcriptional responses, each inducing features of starvation response. In contrast to their comparable effects on gene expression, lactic acidosis and glucose deprivation have opposing effects on glucose uptake. This divergence of metabolic responses in the context of highly similar transcriptional responses allows the identification of a small subset of genes that are regulated in opposite directions by these two conditions. Among these selected genes, TXNIP and its paralogue ARRDC4 are both induced under lactic acidosis and repressed with glucose deprivation. This induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA:Mlx, which is usually triggered upon glucose exposure. Therefore, the upregulation of TXNIP significantly contributes to inhibition of tumor glycolytic phenotypes under lactic acidosis. Expression levels of TXNIP and ARRDC4 in human cancers are also highly correlated with predicted lactic acidosis pathway activities and associated with favorable clinical outcomes. Lactic acidosis triggers features of starvation response while activating the glucose-sensing MondoA-TXNIP pathways and contributing to the "anti-Warburg" metabolic effects and anti-tumor properties of cancer cells. These results stem from integrative analysis of transcriptome and metabolic response data under various tumor microenvironmental stresses and open new paths to explore how these stresses influence phenotypic and metabolic adaptations in human cancers.

Authors
Chen, JL-Y; Merl, D; Peterson, CW; Wu, J; Liu, PY; Yin, H; Muoio, DM; Ayer, DE; West, M; Chi, J-T
MLA Citation
Chen, JL-Y, Merl, D, Peterson, CW, Wu, J, Liu, PY, Yin, H, Muoio, DM, Ayer, DE, West, M, and Chi, J-T. "Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA. (Published online)" PLoS Genet 6.9 (September 2, 2010): e1001093-.
Website
http://hdl.handle.net/10161/4477
PMID
20844768
Source
pubmed
Published In
PLoS genetics
Volume
6
Issue
9
Publish Date
2010
Start Page
e1001093
DOI
10.1371/journal.pgen.1001093

Metabolic profiling of muscle contraction in lean compared with obese rodents.

Interest in the pathophysiological relevance of intramuscular triacylglycerol (IMTG) accumulation has grown from numerous studies reporting that abnormally high glycerolipid levels in tissues of obese and diabetic subjects correlate negatively with glucose tolerance. Here, we used a hindlimb perfusion model to examine the impact of obesity and elevated IMTG levels on contraction-induced changes in skeletal muscle fuel metabolism. Comprehensive lipid profiling was performed on gastrocnemius muscles harvested from lean and obese Zucker rats immediately and 25 min after 15 min of one-legged electrically stimulated contraction compared with the contralateral control (rested) limbs. Predictably, IMTG content was grossly elevated in control muscles from obese rats compared with their lean counterparts. In muscles of obese (but not lean) rats, contraction resulted in marked hydrolysis of IMTG, which was then restored to near resting levels during 25 min of recovery. Despite dramatic phenotypical differences in contraction-induced IMTG turnover, muscle levels of diacylglycerol (DAG) and long-chain acyl-CoAs (LCACoA) were surprisingly similar between groups. Tissue profiles of acylcarnitine metabolites suggested that the surfeit of IMTG in obese rats fueled higher rates of fat oxidation relative to the lean group. Muscles of the obese rats had reduced lactate levels immediately following contraction and higher glycogen resynthesis during recovery, consistent with a lipid-associated glucose-sparing effect. Together, these findings suggest that contraction-induced mobilization of local lipid reserves in obese muscles promotes beta-oxidation, while discouraging glucose utilization. Further studies are necessary to determine whether persistent oxidation of IMTG-derived fatty acids contributes to systemic glucose intolerance in other physiological settings.

Authors
Thyfault, JP; Cree, MG; Tapscott, EB; Bell, JA; Koves, TR; Ilkayeva, O; Wolfe, RR; Dohm, GL; Muoio, DM
MLA Citation
Thyfault, JP, Cree, MG, Tapscott, EB, Bell, JA, Koves, TR, Ilkayeva, O, Wolfe, RR, Dohm, GL, and Muoio, DM. "Metabolic profiling of muscle contraction in lean compared with obese rodents." Am J Physiol Regul Integr Comp Physiol 299.3 (September 2010): R926-R934.
PMID
20504904
Source
pubmed
Published In
American journal of physiology. Regulatory, integrative and comparative physiology
Volume
299
Issue
3
Publish Date
2010
Start Page
R926
End Page
R934
DOI
10.1152/ajpregu.00093.2010

Metabolism and vascular fatty acid transport.

Authors
Muoio, DM
MLA Citation
Muoio, DM. "Metabolism and vascular fatty acid transport." N Engl J Med 363.3 (July 15, 2010): 291-293.
PMID
20647206
Source
pubmed
Published In
The New England journal of medicine
Volume
363
Issue
3
Publish Date
2010
Start Page
291
End Page
293
DOI
10.1056/NEJMcibr1005397

Adipose acyl-CoA synthetase-1 directs fatty acids toward beta-oxidation and is required for cold thermogenesis.

Long-chain acyl-CoA synthetase-1 (ACSL1) contributes 80% of total ACSL activity in adipose tissue and was believed to be essential for the synthesis of triacylglycerol. We predicted that an adipose-specific knockout of ACSL1 (Acsl1(A-/-)) would be lipodystrophic, but compared to controls, Acsl1(A-/-) mice had 30% greater fat mass when fed a low-fat diet and gained weight normally when fed a high-fat diet. Acsl1(A-/-) adipocytes incorporated [(14)C]oleate into glycerolipids normally, but fatty acid (FA) oxidation rates were 50%-90% lower than in control adipocytes and mitochondria. Acsl1(A-/-) mice were markedly cold intolerant, and beta(3)-adrenergic agonists did not increase oxygen consumption, despite normal adrenergic signaling in brown adipose tissue. The reduced adipose FA oxidation and marked cold intolerance of Acsl1(A-/-) mice indicate that normal activation of FA for oxidation in adipose tissue in vivo requires ACSL1. Thus, ACSL1 has a specific function in directing the metabolic partitioning of FAs toward beta-oxidation in adipocytes.

Authors
Ellis, JM; Li, LO; Wu, P-C; Koves, TR; Ilkayeva, O; Stevens, RD; Watkins, SM; Muoio, DM; Coleman, RA
MLA Citation
Ellis, JM, Li, LO, Wu, P-C, Koves, TR, Ilkayeva, O, Stevens, RD, Watkins, SM, Muoio, DM, and Coleman, RA. "Adipose acyl-CoA synthetase-1 directs fatty acids toward beta-oxidation and is required for cold thermogenesis." Cell Metab 12.1 (July 7, 2010): 53-64.
PMID
20620995
Source
pubmed
Published In
Cell Metabolism
Volume
12
Issue
1
Publish Date
2010
Start Page
53
End Page
64
DOI
10.1016/j.cmet.2010.05.012

Lipid partitioning, incomplete fatty acid oxidation, and insulin signal transduction in primary human muscle cells: effects of severe obesity, fatty acid incubation, and fatty acid translocase/CD36 overexpression.

CONTEXT: Intracellular lipid partitioning toward storage and the incomplete oxidation of fatty acids (FA) have been linked to insulin resistance. OBJECTIVE: To gain insight into how intracellular lipid metabolism is related to insulin signal transduction, we examined the effects of severe obesity, excess FA, and overexpression of the FA transporter, FA translocase (FAT)/CD36, in primary human skeletal myocytes. DESIGN, SETTING, AND PATIENTS: Insulin signal transduction, FA oxidation, and metabolism were measured in skeletal muscle cells harvested from lean and severely obese women. To emulate the obesity phenotype in our cell culture system, we incubated cells from lean individuals with excess FA or overexpressed FAT/CD36 using recombinant adenoviral technology. RESULTS: Complete oxidation of FA was significantly reduced, whereas total lipid accumulation, FA esterification into lipid intermediates, and incomplete oxidation were up-regulated in the muscle cells of severely obese subjects. Insulin signal transduction was reduced in the muscle cells from severely obese subjects compared to lean controls. Incubation of muscle cells from lean subjects with lipids reduced insulin signal transduction and increased lipid storage and incomplete FA oxidation. CD36 overexpression increased FA transport capacity, but did not impair complete FA oxidation and insulin signal transduction in muscle cells from lean subjects. CONCLUSIONS: Cultured myocytes from severely obese women express perturbations in FA metabolism and insulin signaling reminiscent of those observed in vivo. The obesity phenotype can be recapitulated in muscle cells from lean subjects via exposure to excess lipid, but not by overexpressing the FAT/CD36 FA transporter.

Authors
Bell, JA; Reed, MA; Consitt, LA; Martin, OJ; Haynie, KR; Hulver, MW; Muoio, DM; Dohm, GL
MLA Citation
Bell, JA, Reed, MA, Consitt, LA, Martin, OJ, Haynie, KR, Hulver, MW, Muoio, DM, and Dohm, GL. "Lipid partitioning, incomplete fatty acid oxidation, and insulin signal transduction in primary human muscle cells: effects of severe obesity, fatty acid incubation, and fatty acid translocase/CD36 overexpression." J Clin Endocrinol Metab 95.7 (July 2010): 3400-3410.
PMID
20427507
Source
pubmed
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
95
Issue
7
Publish Date
2010
Start Page
3400
End Page
3410
DOI
10.1210/jc.2009-1596

Alterations in skeletal muscle fatty acid handling predisposes middle-aged mice to diet-induced insulin resistance.

OBJECTIVE: Although advanced age is a risk factor for type 2 diabetes, a clear understanding of the changes that occur during middle age that contribute to the development of skeletal muscle insulin resistance is currently lacking. Therefore, we sought to investigate how middle age impacts skeletal muscle fatty acid handling and to determine how this contributes to the development of diet-induced insulin resistance. RESEARCH DESIGN AND METHODS: Whole-body and skeletal muscle insulin resistance were studied in young and middle-aged wild-type and CD36 knockout (KO) mice fed either a standard or a high-fat diet for 12 weeks. Molecular signaling pathways, intramuscular triglycerides accumulation, and targeted metabolomics of in vivo mitochondrial substrate flux were also analyzed in the skeletal muscle of mice of all ages. RESULTS: Middle-aged mice fed a standard diet demonstrated an increase in intramuscular triglycerides without a concomitant increase in insulin resistance. However, middle-aged mice fed a high-fat diet were more susceptible to the development of insulin resistance-a condition that could be prevented by limiting skeletal muscle fatty acid transport and excessive lipid accumulation in middle-aged CD36 KO mice. CONCLUSION: Our data provide insight into the mechanisms by which aging becomes a risk factor for the development of insulin resistance. Our data also demonstrate that limiting skeletal muscle fatty acid transport is an effective approach for delaying the development of age-associated insulin resistance and metabolic disease during exposure to a high-fat diet.

Authors
Koonen, DPY; Sung, MMY; Kao, CKC; Dolinsky, VW; Koves, TR; Ilkayeva, O; Jacobs, RL; Vance, DE; Light, PE; Muoio, DM; Febbraio, M; Dyck, JRB
MLA Citation
Koonen, DPY, Sung, MMY, Kao, CKC, Dolinsky, VW, Koves, TR, Ilkayeva, O, Jacobs, RL, Vance, DE, Light, PE, Muoio, DM, Febbraio, M, and Dyck, JRB. "Alterations in skeletal muscle fatty acid handling predisposes middle-aged mice to diet-induced insulin resistance." Diabetes 59.6 (June 2010): 1366-1375.
PMID
20299464
Source
pubmed
Published In
Diabetes
Volume
59
Issue
6
Publish Date
2010
Start Page
1366
End Page
1375
DOI
10.2337/db09-1142

Peroxisome proliferator-activated receptor-gamma coactivator-1alpha overexpression increases lipid oxidation in myocytes from extremely obese individuals.

OBJECTIVE: To determine whether the obesity-related decrement in fatty acid oxidation (FAO) in primary human skeletal muscle cells (HSkMC) is linked with lower mitochondrial content and whether this deficit could be corrected via overexpression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha). RESEARCH DESIGN AND METHODS: FAO was studied in HSkMC from lean (BMI 22.4 +/- 0.9 kg/m(2); N = 12) and extremely obese (45.3 +/- 1.4 kg/m(2); N = 9) subjects. Recombinant adenovirus was used to increase HSkMC PGC-1alpha expression (3.5- and 8.0-fold), followed by assessment of mitochondrial content (mtDNA and cytochrome C oxidase IV [COXIV]), complete ((14)CO(2) production from labeled oleate), and incomplete (acid soluble metabolites [ASM]) FAO, and glycerolipid synthesis. RESULTS: Obesity was associated with a 30% decrease (P < 0.05) in complete FAO, which was accompanied by higher relative rates of incomplete FAO ([(14)C]ASM production/(14)CO(2)), increased partitioning of fatty acid toward storage, and lower (P < 0.05) mtDNA (-27%), COXIV (-35%), and mitochondrial transcription factor (mtTFA) (-43%) protein levels. PGC-1alpha overexpression increased (P < 0.05) FAO, mtDNA, COXIV, mtTFA, and fatty acid incorporation into triacylglycerol in both lean and obese groups. Perturbations in FAO, triacylglycerol synthesis, mtDNA, COXIV, and mtTFA in obese compared with lean HSkMC persisted despite PGC-1alpha overexpression. When adjusted for mtDNA and COXIV content, FAO was equivalent between lean and obese groups. CONCLUSION: Reduced mitochondrial content is related to impaired FAO in HSkMC derived from obese individuals. Increasing PGC-1alpha protein levels did not correct the obesity-related absolute reduction in FAO or mtDNA content, implicating mechanisms other than PGC-1alpha abundance.

Authors
Consitt, LA; Bell, JA; Koves, TR; Muoio, DM; Hulver, MW; Haynie, KR; Dohm, GL; Houmard, JA
MLA Citation
Consitt, LA, Bell, JA, Koves, TR, Muoio, DM, Hulver, MW, Haynie, KR, Dohm, GL, and Houmard, JA. "Peroxisome proliferator-activated receptor-gamma coactivator-1alpha overexpression increases lipid oxidation in myocytes from extremely obese individuals." Diabetes 59.6 (June 2010): 1407-1415.
PMID
20200320
Source
pubmed
Published In
Diabetes
Volume
59
Issue
6
Publish Date
2010
Start Page
1407
End Page
1415
DOI
10.2337/db09-1704

Caloric restriction, aerobic exercise or a combination improves metabolic profiles following diet-induced obesity

Authors
Glynn, EL; An, J; Wang, L-P; Ilkayeva, OR; Stevens, RD; Bain, JR; Muehlbauer, MJ; Koves, TR; Summers, SA; Muoio, DM; Newgard, CB
MLA Citation
Glynn, EL, An, J, Wang, L-P, Ilkayeva, OR, Stevens, RD, Bain, JR, Muehlbauer, MJ, Koves, TR, Summers, SA, Muoio, DM, and Newgard, CB. "Caloric restriction, aerobic exercise or a combination improves metabolic profiles following diet-induced obesity." FASEB JOURNAL 24 (April 2010).
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
24
Publish Date
2010

Loss of ovarian function alters multiple aspects of lipid metabolism in adipose tissue and skeletal muscle from female mice.

Authors
Spangenburg, EE; Campbell, KM; Wohlers, LM; Maher, AC; Koves, TK; Bonen, A; Muoio, DM
MLA Citation
Spangenburg, EE, Campbell, KM, Wohlers, LM, Maher, AC, Koves, TK, Bonen, A, and Muoio, DM. "Loss of ovarian function alters multiple aspects of lipid metabolism in adipose tissue and skeletal muscle from female mice." FASEB JOURNAL 24 (April 2010).
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
24
Publish Date
2010

Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused?

The term lipotoxicity elicits visions of steatotic liver, fat laden skeletal muscles and engorged lipid droplets that spawn a number of potentially harmful intermediates that can wreak havoc on signal transduction and organ function. Prominent among these so-called lipotoxic mediators are signaling molecules such as long chain acyl-CoAs, ceramides and diacyglycerols; each of which is thought to engage serine kinases that disrupt the insulin signaling cascade, thereby causing insulin resistance. Defects in skeletal muscle fat oxidation have been implicated as a driving factor contributing to systemic lipid imbalance, whereas exercise-induced enhancement of oxidative potential is considered protective. The past decade of diabetes research has focused heavily on the foregoing scenario, and indeed the model is grounded in strong experimental evidence, albeit largely correlative. This review centers on mechanisms that connect lipid surplus to insulin resistance in skeletal muscle, as well as those that underlie the antilipotoxic actions of exercise. Emphasis is placed on recent studies that challenge accepted paradigms.

Authors
Muoio, DM
MLA Citation
Muoio, DM. "Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused?." Biochim Biophys Acta 1801.3 (March 2010): 281-288. (Review)
PMID
19958841
Source
pubmed
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
1801
Issue
3
Publish Date
2010
Start Page
281
End Page
288
DOI
10.1016/j.bbalip.2009.11.007

Downregulation of adipose glutathione S-tansferase A4 leads to increased protein carbonylation, oxidative stress, and mitochondrial dysfunction

OBJECTIVE - Peripheral insulin resistance is linked to an increase in reactive oxygen species (ROS), leading in part to the production of reactive lipid aldehydes that modify the side chains of protein amino acids in a reaction termed protein carbonylation. The primary enzymatic method for lipid aldehyde detoxification is via glutathione S-transferase A4 (GSTA4) dependent glutathionylation. The objective of this study was to evaluate the expression of GSTA4 and the role(s) of protein carbonylation in adipocyte function. RESEARCH DESIGN AND METHODS - GSTA4-silenced 3T3-L1 adipocytes and GSTA4-null mice were evaluated for metabolic processes, mitochondrial function, and reactive oxygen species production. GSTA4 expression in human obesity was evaluated using microarray analysis. RESULTS - GSTA4 expression is selectively downregulated in adipose tissue of obese insulin-resistant C57BL/6J mice and in human obesity-linked insulin resistance. Tumor necrosis factor-α treatment of 3T3-L1 adipocytes decreased GSTA4 expression, and silencing GSTA4 mRNA in cultured adipocytes resulted in increased protein carbonylation, increased mitochondrial ROS, dysfunctional state 3 respiration, and altered glucose transport and lipolysis. Mitochondrial function in adipocytes of lean or obese GSTA4-null mice was significantly compromised compared with wild-type controls and was accompanied by an increase in superoxide anion. CONCLUSIONS - These results indicate that downregulation of GSTA4 in adipose tissue leads to increased protein carbonylation, ROS production, and mitochondrial dysfunction and may contribute to the development of insulin resistance and type 2 diabetes. © 2010 by the American Diabetes Association.

Authors
Curtis, JM; Grimsrud, PA; Wright, WS; Xu, X; Foncea, RE; Graham, DW; Brestoff, JR; Wiczer, BM; Ilkayeva, O; Cianflone, K; Muoio, DE; Arriaga, EA; Bernlohr, DA
MLA Citation
Curtis, JM, Grimsrud, PA, Wright, WS, Xu, X, Foncea, RE, Graham, DW, Brestoff, JR, Wiczer, BM, Ilkayeva, O, Cianflone, K, Muoio, DE, Arriaga, EA, and Bernlohr, DA. "Downregulation of adipose glutathione S-tansferase A4 leads to increased protein carbonylation, oxidative stress, and mitochondrial dysfunction." Diabetes 59.5 (2010): 1132-1142.
PMID
20150287
Source
scival
Published In
Diabetes
Volume
59
Issue
5
Publish Date
2010
Start Page
1132
End Page
1142
DOI
10.2337/db09-1105

Metabolomics applied to diabetes research: moving from information to knowledge.

Authors
Bain, JR; Stevens, RD; Wenner, BR; Ilkayeva, O; Muoio, DM; Newgard, CB
MLA Citation
Bain, JR, Stevens, RD, Wenner, BR, Ilkayeva, O, Muoio, DM, and Newgard, CB. "Metabolomics applied to diabetes research: moving from information to knowledge." Diabetes 58.11 (November 2009): 2429-2443.
PMID
19875619
Source
pubmed
Published In
Diabetes
Volume
58
Issue
11
Publish Date
2009
Start Page
2429
End Page
2443
DOI
10.2337/db09-0580

Liver-specific loss of long chain acyl-CoA synthetase-1 decreases triacylglycerol synthesis and beta-oxidation and alters phospholipid fatty acid composition.

In mammals, a family of five acyl-CoA synthetases (ACSLs), each the product of a separate gene, activates long chain fatty acids to form acyl-CoAs. Because the ACSL isoforms have overlapping preferences for fatty acid chain length and saturation and are expressed in many of the same tissues, the individual function of each isoform has remained uncertain. Thus, we constructed a mouse model with a liver-specific knock-out of ACSL1, a major ACSL isoform in liver. Eliminating ACSL1 in liver resulted in a 50% decrease in total hepatic ACSL activity and a 25-35% decrease in long chain acyl-CoA content. Although the content of triacylglycerol was unchanged in Acsl1(L)(-/-) liver after mice were fed either low or high fat diets, in isolated primary hepatocytes the absence of ACSL1 diminished the incorporation of [(14)C]oleate into triacylglycerol. Further, small but consistent increases were observed in the percentage of 16:0 in phosphatidylcholine and phosphatidylethanolamine and of 18:1 in phosphatidylethanolamine and lysophosphatidylcholine, whereas concomitant decreases were seen in 18:0 in phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and lysophosphatidylcholine. In addition, decreases in long chain acylcarnitine content and diminished production of acid-soluble metabolites from [(14)C]oleate suggested that hepatic ACSL1 is important for mitochondrial beta-oxidation of long chain fatty acids. Because the Acsl1(L)(-/-) mice were not protected from developing either high fat diet-induced hepatic steatosis or insulin resistance, our study suggests that lowering the content of hepatic acyl-CoA without a concomitant decrease in triacylglycerol and other lipid intermediates is insufficient to protect against hepatic insulin resistance.

Authors
Li, LO; Ellis, JM; Paich, HA; Wang, S; Gong, N; Altshuller, G; Thresher, RJ; Koves, TR; Watkins, SM; Muoio, DM; Cline, GW; Shulman, GI; Coleman, RA
MLA Citation
Li, LO, Ellis, JM, Paich, HA, Wang, S, Gong, N, Altshuller, G, Thresher, RJ, Koves, TR, Watkins, SM, Muoio, DM, Cline, GW, Shulman, GI, and Coleman, RA. "Liver-specific loss of long chain acyl-CoA synthetase-1 decreases triacylglycerol synthesis and beta-oxidation and alters phospholipid fatty acid composition." J Biol Chem 284.41 (October 9, 2009): 27816-27826.
PMID
19648649
Source
pubmed
Published In
The Journal of biological chemistry
Volume
284
Issue
41
Publish Date
2009
Start Page
27816
End Page
27826
DOI
10.1074/jbc.M109.022467

ALTERATIONS IN MITOCHONDRIAL FUEL METABOLISM AND SURVIVAL WITH REDUCED MANGANESE SUPEROXIDE DISMUTASE (SOD2)

Authors
Lum, H; Koves, TR; DeBalsi, KL; Ilkayeva, O; Van Remmen, H; Muoio, DM
MLA Citation
Lum, H, Koves, TR, DeBalsi, KL, Ilkayeva, O, Van Remmen, H, and Muoio, DM. "ALTERATIONS IN MITOCHONDRIAL FUEL METABOLISM AND SURVIVAL WITH REDUCED MANGANESE SUPEROXIDE DISMUTASE (SOD2)." GERONTOLOGIST 49 (October 2009): 25-25.
Source
wos-lite
Published In
The Gerontologist
Volume
49
Publish Date
2009
Start Page
25
End Page
25

Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control.

In addition to its essential role in permitting mitochondrial import and oxidation of long chain fatty acids, carnitine also functions as an acyl group acceptor that facilitates mitochondrial export of excess carbons in the form of acylcarnitines. Recent evidence suggests carnitine requirements increase under conditions of sustained metabolic stress. Accordingly, we hypothesized that carnitine insufficiency might contribute to mitochondrial dysfunction and obesity-related impairments in glucose tolerance. Consistent with this prediction whole body carnitine diminution was identified as a common feature of insulin-resistant states such as advanced age, genetic diabetes, and diet-induced obesity. In rodents fed a lifelong (12 month) high fat diet, compromised carnitine status corresponded with increased skeletal muscle accumulation of acylcarnitine esters and diminished hepatic expression of carnitine biosynthetic genes. Diminished carnitine reserves in muscle of obese rats was accompanied by marked perturbations in mitochondrial fuel metabolism, including low rates of complete fatty acid oxidation, elevated incomplete beta-oxidation, and impaired substrate switching from fatty acid to pyruvate. These mitochondrial abnormalities were reversed by 8 weeks of oral carnitine supplementation, in concert with increased tissue efflux and urinary excretion of acetylcarnitine and improvement of whole body glucose tolerance. Acetylcarnitine is produced by the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT). A role for this enzyme in combating glucose intolerance was further supported by the finding that CrAT overexpression in primary human skeletal myocytes increased glucose uptake and attenuated lipid-induced suppression of glucose oxidation. These results implicate carnitine insufficiency and reduced CrAT activity as reversible components of the metabolic syndrome.

Authors
Noland, RC; Koves, TR; Seiler, SE; Lum, H; Lust, RM; Ilkayeva, O; Stevens, RD; Hegardt, FG; Muoio, DM
MLA Citation
Noland, RC, Koves, TR, Seiler, SE, Lum, H, Lust, RM, Ilkayeva, O, Stevens, RD, Hegardt, FG, and Muoio, DM. "Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control." J Biol Chem 284.34 (August 21, 2009): 22840-22852.
PMID
19553674
Source
pubmed
Published In
The Journal of biological chemistry
Volume
284
Issue
34
Publish Date
2009
Start Page
22840
End Page
22852
DOI
10.1074/jbc.M109.032888

Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase.

OBJECTIVE: Whereas an impaired ability to oxidize fatty acids is thought to contribute to intracellular lipid accumulation, insulin resistance, and cardiac dysfunction, high rates of fatty acid oxidation could also impair glucose metabolism and function. We therefore determined the effects of diet-induced obesity (DIO) in wild-type (WT) mice and mice deficient for malonyl CoA decarboxylase (MCD(-/-); an enzyme promoting mitochondrial fatty acid oxidation) on insulin-sensitive cardiac glucose oxidation. RESEARCH DESIGN AND METHODS: WT and MCD(-/-) mice were fed a low- or high-fat diet for 12 weeks, and intramyocardial lipid metabolite accumulation was assessed. A parallel feeding study was performed to assess myocardial function and energy metabolism (nanomoles per gram of dry weight per minute) in isolated working hearts (+/- insulin). RESULTS: DIO markedly reduced insulin-stimulated glucose oxidation compared with low fat-fed WT mice (167 +/- 31 vs. 734 +/- 125; P < 0.05). MCD(-/-) mice subjected to DIO displayed a more robust insulin-stimulated glucose oxidation (554 +/- 82 vs. 167 +/- 31; P < 0.05) and less incomplete fatty acid oxidation, evidenced by a decrease in long-chain acylcarnitines compared with WT counterparts. MCD(-/-) mice had long-chain acyl CoAs similar to those of WT mice subjected to DIO but had increased triacylglycerol levels (10.92 +/- 3.72 vs. 3.29 +/- 0.62 mumol/g wet wt; P < 0.05). CONCLUSIONS: DIO does not impair cardiac fatty acid oxidation or function, and there exists disassociation between myocardial lipid accumulation and insulin sensitivity. Our results suggest that MCD deficiency is not detrimental to the heart in obesity.

Authors
Ussher, JR; Koves, TR; Jaswal, JS; Zhang, L; Ilkayeva, O; Dyck, JRB; Muoio, DM; Lopaschuk, GD
MLA Citation
Ussher, JR, Koves, TR, Jaswal, JS, Zhang, L, Ilkayeva, O, Dyck, JRB, Muoio, DM, and Lopaschuk, GD. "Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase." Diabetes 58.8 (August 2009): 1766-1775.
PMID
19478144
Source
pubmed
Published In
Diabetes
Volume
58
Issue
8
Publish Date
2009
Start Page
1766
End Page
1775
DOI
10.2337/db09-0011

Increased insulin sensitivity in mice lacking collectrin, a downstream target of HNF-1alpha.

Collectrin is a downstream target of the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha), which is mutated in maturity-onset diabetes of the young subtype 3 (MODY3). Evidence from transgenic mouse models with collectrin overexpression in pancreatic islets suggests divergent roles for collectrin in influencing beta-cell mass and insulin exocytosis. To clarify the function of collectrin in the pancreas, we used a mouse line with targeted deletion of the gene. We examined pancreas morphology, glucose homeostasis by ip glucose tolerance testing (IPGTT) and insulin tolerance testing (IPITT), and pancreas function by in vivo acute-phase insulin response determination and glucose-stimulated insulin secretion from isolated islets. We find no difference in either pancreas morphology or function between wild-type and collectrin-deficient animals (Tmem27(-/y)). However, we note that by 6 months of age, Tmem27(-/y) mice exhibit increased insulin sensitivity by IPITT and decreased adiposity by dual-energy x-ray absorptiometry scanning compared with wild-type. We have previously reported that Tmem27(-/y) mice exhibit profound aminoaciduria due to failed renal recovery. We now demonstrate that Tmem27(-/y) animals also display inappropriate excretion of some short-chain acylcarnitines derived from amino acid and fatty acid oxidation. We provide further evidence for compensatory up-regulation of oxidative metabolism in Tmem27(-/y) mice, along with enhanced protein turnover associated with preserved lean mass even out to 1.5 yr of age. Our studies suggest that collectrin-deficient mice activate a number of adaptive mechanisms to defend energy homeostasis in the setting of ongoing nutrient losses.

Authors
Malakauskas, SM; Kourany, WM; Zhang, XY; Lu, D; Stevens, RD; Koves, TR; Hohmeier, HE; Muoio, DM; Newgard, CB; Le, TH
MLA Citation
Malakauskas, SM, Kourany, WM, Zhang, XY, Lu, D, Stevens, RD, Koves, TR, Hohmeier, HE, Muoio, DM, Newgard, CB, and Le, TH. "Increased insulin sensitivity in mice lacking collectrin, a downstream target of HNF-1alpha." Mol Endocrinol 23.6 (June 2009): 881-892.
PMID
19246514
Source
pubmed
Published In
Molecular endocrinology (Baltimore, Md.)
Volume
23
Issue
6
Publish Date
2009
Start Page
881
End Page
892
DOI
10.1210/me.2008-0274

Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation.

Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a master transcriptional regulator of beta-oxidation and a prominent target of hypolipidemic drugs. To gain deeper insights into the systemic consequences of impaired fat catabolism, we used quantitative, mass spectrometry-based metabolic profiling to investigate the fed-to-fasted transition in PPARalpha(+/+) and PPARalpha(-/-) mice. Compared to PPARalpha(+/+) animals, acylcarnitine profiles of PPARalpha(-/-) mice revealed 2- to 4-fold accumulation of long-chain species in the plasma, whereas short-chain species were reduced by as much as 69% in plasma, liver, and skeletal muscle. These results reflect a metabolic bottleneck downstream of carnitine palmitoyltransferase-1, a mitochondrial enzyme that catalyzes the first step in beta-oxidation. Organic and amino acid profiles of starved PPARalpha(-/-) mice suggested compromised citric acid cycle flux, enhanced urea cycle activity, and increased amino acid catabolism. PPARalpha(-/-) mice had 40-50% lower plasma and tissue levels of free carnitine, corresponding with diminished hepatic expression of genes involved in carnitine biosynthesis and transport. One week of oral carnitine supplementation conferred partial metabolic recovery in the PPARalpha(-/-) mice. In summary, comprehensive metabolic profiling revealed novel biomarkers of defective fat oxidation, while also highlighting the potential value of supplemental carnitine as a therapy and diagnostic tool for metabolic disorders.

Authors
Makowski, L; Noland, RC; Koves, TR; Xing, W; Ilkayeva, OR; Muehlbauer, MJ; Stevens, RD; Muoio, DM
MLA Citation
Makowski, L, Noland, RC, Koves, TR, Xing, W, Ilkayeva, OR, Muehlbauer, MJ, Stevens, RD, and Muoio, DM. "Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation." FASEB J 23.2 (February 2009): 586-604.
PMID
18945875
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
23
Issue
2
Publish Date
2009
Start Page
586
End Page
604
DOI
10.1096/fj.08-119420

The STEDMAN project: biophysical, biochemical and metabolic effects of a behavioral weight loss intervention during weight loss, maintenance, and regain.

The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) Project uses comprehensive metabolic profiling to probe biochemical mechanisms of weight loss in humans. Measurements at baseline, 2 and 4 weeks, 6 and 12 months included diet, body composition, metabolic rate, hormones, and 80 intermediary metabolites measured by mass spectrometry. In 27 obese adults in a behavioral weight loss intervention, median weight decreased 13.9 lb over the first 6 months, then reverted towards baseline by 12 months. Insulin resistance (HOMA) was partially ameliorated in the first 6 months and showed sustained improvement at 12 months despite weight regain. Ghrelin increased with weight loss and reverted to baseline, whereas leptin and PYY fell at 6 months and remained persistently low. NPY levels did not change. Factors possibly contributing to sustained improvement in insulin sensitivity despite weight regain include adiponectin (increased by 12 months), IGF-1 (increased during weight loss and continued to increase during weight regain), and visceral fat (fell at 6 months but did not change thereafter). We observed a persistent reduction in free fatty acids, branched chain amino acids, and related metabolites that may contribute to improved insulin action. These findings provide evidence for sustained benefits of weight loss in obese humans and insights into mechanisms.

Authors
Lien, LF; Haqq, AM; Arlotto, M; Slentz, CA; Muehlbauer, MJ; McMahon, RL; Rochon, J; Gallup, D; Bain, JR; Ilkayeva, O; Wenner, BR; Stevens, RD; Millington, DS; Muoio, DM; Butler, MD; Newgard, CB; Svetkey, LP
MLA Citation
Lien, LF, Haqq, AM, Arlotto, M, Slentz, CA, Muehlbauer, MJ, McMahon, RL, Rochon, J, Gallup, D, Bain, JR, Ilkayeva, O, Wenner, BR, Stevens, RD, Millington, DS, Muoio, DM, Butler, MD, Newgard, CB, and Svetkey, LP. "The STEDMAN project: biophysical, biochemical and metabolic effects of a behavioral weight loss intervention during weight loss, maintenance, and regain." OMICS 13.1 (February 2009): 21-35.
PMID
19290809
Source
pubmed
Published In
OMICS: A Journal of Integrative Biology
Volume
13
Issue
1
Publish Date
2009
Start Page
21
End Page
35
DOI
10.1089/omi.2008.0035

Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase (Diabetes (2009) 58, (1766-1775))

Authors
Ussher, JR; Koves, TR; Jaswal, JS; Zhang, L; Ilkayeva, O; Dyck, JRB; Muoio, DM; Lopaschuk, GD
MLA Citation
Ussher, JR, Koves, TR, Jaswal, JS, Zhang, L, Ilkayeva, O, Dyck, JRB, Muoio, DM, and Lopaschuk, GD. "Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase (Diabetes (2009) 58, (1766-1775))." Diabetes 58.10 (2009): 2425--.
Source
scival
Published In
Diabetes
Volume
58
Issue
10
Publish Date
2009
Start Page
2425-

Insulin-Stimulated Glucose Oxidation is Increased in Hearts from High Fat Diet-Induced Obese Mice Lacking Malonyl CoA Decarboxylase

Authors
Ussher, JER; Koves, TR; Jaswal, JS; Newgard, CB; Dyck, JR; Muoio, DM; Lopaschuk, GD
MLA Citation
Ussher, JER, Koves, TR, Jaswal, JS, Newgard, CB, Dyck, JR, Muoio, DM, and Lopaschuk, GD. "Insulin-Stimulated Glucose Oxidation is Increased in Hearts from High Fat Diet-Induced Obese Mice Lacking Malonyl CoA Decarboxylase." CIRCULATION 118.18 (October 28, 2008): S539-S539.
Source
wos-lite
Published In
Circulation
Volume
118
Issue
18
Publish Date
2008
Start Page
S539
End Page
S539

Fatty acid oxidation and insulin action: when less is more.

Authors
Muoio, DM; Newgard, CB
MLA Citation
Muoio, DM, and Newgard, CB. "Fatty acid oxidation and insulin action: when less is more." Diabetes 57.6 (June 2008): 1455-1456.
PMID
18511446
Source
pubmed
Published In
Diabetes
Volume
57
Issue
6
Publish Date
2008
Start Page
1455
End Page
1456
DOI
10.2337/db08-0281

Metabolic crosstalk between human skeletal myocytes and co-cultured adipocytes

Authors
Kovalik, J-P; Noland, RC; Ilkayeva, O; Muoio, DM
MLA Citation
Kovalik, J-P, Noland, RC, Ilkayeva, O, and Muoio, DM. "Metabolic crosstalk between human skeletal myocytes and co-cultured adipocytes." June 2008.
Source
wos-lite
Published In
Diabetes
Volume
57
Publish Date
2008
Start Page
A392
End Page
A393

Glucose sensing by MondoA:Mlx complexes: a role for hexokinases and direct regulation of thioredoxin-interacting protein expression.

Glucose is a fundamental metabolite, yet how cells sense and respond to changes in extracellular glucose concentration is not completely understood. We recently reported that the MondoA:Mlx dimeric transcription factor directly regulates glycolysis. In this article, we consider whether MondoA:Mlx complexes have a broader role in sensing and responding to glucose status. In their latent state, MondoA:Mlx complexes localize to the outer mitochondrial membrane, yet shuttle between the mitochondria and the nucleus. We show that MondoA:Mlx complexes accumulate in the nucleus in response to glucose and 2-deoxyglucose (2-DG). Furthermore, nuclear localization of MondoA:Mlx depends on the enzymatic activity of hexokinases. These enzymes catalyze conversion of glucose to glucose-6-phosphate (G6P), which is the first step in the glycolytic pathway. Together, these findings suggest that MondoA:Mlx monitors intracellular G6P concentration and translocates to the nucleus when levels of this key metabolite increase. Transcriptional profiling experiments demonstrate that MondoA is required for >75% of the 2-DG-induced transcription signature. We identify thioredoxin-interacting protein (TXNIP) as a direct and glucose-regulated MondoA:Mlx transcriptional target. Furthermore, MondoA:Mlx complexes, via their regulation of TXNIP, are potent negative regulators of glucose uptake. These studies suggest a key role for MondoA:Mlx complexes in the adaptive transcriptional response to changes in extracellular glucose concentration and peripheral glucose uptake.

Authors
Stoltzman, CA; Peterson, CW; Breen, KT; Muoio, DM; Billin, AN; Ayer, DE
MLA Citation
Stoltzman, CA, Peterson, CW, Breen, KT, Muoio, DM, Billin, AN, and Ayer, DE. "Glucose sensing by MondoA:Mlx complexes: a role for hexokinases and direct regulation of thioredoxin-interacting protein expression." Proc Natl Acad Sci U S A 105.19 (May 13, 2008): 6912-6917.
PMID
18458340
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
105
Issue
19
Publish Date
2008
Start Page
6912
End Page
6917
DOI
10.1073/pnas.0712199105

Fatty acid transporter expression in human myocytes

Authors
Bell, JA; Reed, MA; Muoio, DM; Dohm, GL
MLA Citation
Bell, JA, Reed, MA, Muoio, DM, and Dohm, GL. "Fatty acid transporter expression in human myocytes." FASEB JOURNAL 22 (April 2008).
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
22
Publish Date
2008

Mechanisms of disease:Molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes.

Nearly unlimited supplies of energy-dense foods and technologies that encourage sedentary behaviour have introduced a new threat to the survival of our species: obesity and its co-morbidities. Foremost among the co-morbidities is type 2 diabetes, which is projected to afflict 300 million people worldwide by 2020. Compliance with lifestyle modifications such as reduced caloric intake and increased physical activity has proved to be difficult for the general population, meaning that pharmacological intervention may be the only recourse for some. This epidemiological reality heightens the urgency for gaining a deeper understanding of the processes that cause metabolic failure of key tissues and organ systems in type 2 diabetes, as reviewed here.

Authors
Muoio, DM; Newgard, CB
MLA Citation
Muoio, DM, and Newgard, CB. "Mechanisms of disease:Molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes." Nat Rev Mol Cell Biol 9.3 (March 2008): 193-205. (Review)
PMID
18200017
Source
pubmed
Published In
Nature Reviews Molecular Cell Biology
Volume
9
Issue
3
Publish Date
2008
Start Page
193
End Page
205
DOI
10.1038/nrm2327

Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance.

Previous studies have suggested that insulin resistance develops secondary to diminished fat oxidation and resultant accumulation of cytosolic lipid molecules that impair insulin signaling. Contrary to this model, the present study used targeted metabolomics to find that obesity-related insulin resistance in skeletal muscle is characterized by excessive beta-oxidation, impaired switching to carbohydrate substrate during the fasted-to-fed transition, and coincident depletion of organic acid intermediates of the tricarboxylic acid cycle. In cultured myotubes, lipid-induced insulin resistance was prevented by manipulations that restrict fatty acid uptake into mitochondria. These results were recapitulated in mice lacking malonyl-CoA decarboxylase (MCD), an enzyme that promotes mitochondrial beta-oxidation by relieving malonyl-CoA-mediated inhibition of carnitine palmitoyltransferase 1. Thus, mcd(-/-) mice exhibit reduced rates of fat catabolism and resist diet-induced glucose intolerance despite high intramuscular levels of long-chain acyl-CoAs. These findings reveal a strong connection between skeletal muscle insulin resistance and lipid-induced mitochondrial stress.

Authors
Koves, TR; Ussher, JR; Noland, RC; Slentz, D; Mosedale, M; Ilkayeva, O; Bain, J; Stevens, R; Dyck, JRB; Newgard, CB; Lopaschuk, GD; Muoio, DM
MLA Citation
Koves, TR, Ussher, JR, Noland, RC, Slentz, D, Mosedale, M, Ilkayeva, O, Bain, J, Stevens, R, Dyck, JRB, Newgard, CB, Lopaschuk, GD, and Muoio, DM. "Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance." Cell Metab 7.1 (January 2008): 45-56.
PMID
18177724
Source
pubmed
Published In
Cell Metabolism
Volume
7
Issue
1
Publish Date
2008
Start Page
45
End Page
56
DOI
10.1016/j.cmet.2007.10.013

Mechanisms of disease : molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes

Authors
MUOIO, D
MLA Citation
MUOIO, D. "Mechanisms of disease : molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes." Nat Rev Mol Cell Biol 9 (2008): 193-205.
Source
cinii-english
Published In
Nat Rev Mol Cell Biol
Volume
9
Publish Date
2008
Start Page
193
End Page
205

Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1 alpha: implications for metabolic disease.

Dyslipidemia and intramuscular accumulation of fatty acid metabolites are increasingly recognized as core features of obesity and type 2 diabetes. Emerging evidence suggests that normal physiological adaptations to a heavy lipid load depend on the coordinated actions of broad transcriptional regulators such as the peroxisome proliferator activated receptors (PPARs) and PPAR gamma coactivator 1 alpha (PGC1 alpha). The application of transcriptomics and targeted metabolic profiling tools based on mass spectrometry has led to our finding that lipid-induced insulin resistance is a condition in which upregulation of PPAR-targeted genes and high rates of beta-oxidation are not supported by a commensurate upregulation of tricarboxylic acid (TCA) cycle activity. In contrast, exercise training enhances mitochondrial performance, favoring tighter coupling between beta-oxidation and the TCA cycle, and concomitantly restores insulin sensitivity in animals fed a chronic high-fat diet. The exercise-activated transcriptional coactivator, PGC1 alpha, plays a key role in coordinating metabolic flux through these 2 intersecting metabolic pathways, and its suppression by overfeeding may contribute to diet-induced mitochondrial dysfunction. Our emerging model predicts that muscle insulin resistance arises from a mitochondrial disconnect between beta-oxidation and TCA cycle activity. Understanding of this "disconnect" and its molecular basis may lead to new therapeutic approaches to combatting metabolic disease.

Authors
Muoio, DM; Koves, TR
MLA Citation
Muoio, DM, and Koves, TR. "Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1 alpha: implications for metabolic disease." Appl Physiol Nutr Metab 32.5 (October 2007): 874-883. (Review)
PMID
18059612
Source
pubmed
Published In
Applied Physiology, Nutrition and Metabolism
Volume
32
Issue
5
Publish Date
2007
Start Page
874
End Page
883
DOI
10.1139/H07-083

TXNIP links redox circuitry to glucose control.

Thioredoxin-interacting protein (TXNIP) binds and inhibits the reducing activity of thioredoxin. A new study (Parikh et al., 2007) implicates this redox rheostat as a negative regulator of peripheral glucose metabolism in humans. Investigators combined human physiology, genomic screening, and cell-based genetic studies to highlight TNXIP as a potential culprit in the pathogenesis of type 2 diabetes.

Authors
Muoio, DM
MLA Citation
Muoio, DM. "TXNIP links redox circuitry to glucose control." Cell Metab 5.6 (June 2007): 412-414.
PMID
17550776
Source
pubmed
Published In
Cell Metabolism
Volume
5
Issue
6
Publish Date
2007
Start Page
412
End Page
414
DOI
10.1016/j.cmet.2007.05.011

Regulation of lipid deposition in primary myocytes of lean and obese subjects

Authors
Bell, JA; Martin, OJ; Reed, MA; Bonen, A; Muoio, DM; Dohm, GL
MLA Citation
Bell, JA, Martin, OJ, Reed, MA, Bonen, A, Muoio, DM, and Dohm, GL. "Regulation of lipid deposition in primary myocytes of lean and obese subjects." June 2007.
Source
wos-lite
Published In
Diabetes
Volume
56
Publish Date
2007
Start Page
A99
End Page
A99

Lipid loading alters metabolic function of primary human adipocytes grown in culture

Authors
Fitzpatrick, LL; Kovalik, J-P; Buehrer, B; Muoio, DM
MLA Citation
Fitzpatrick, LL, Kovalik, J-P, Buehrer, B, and Muoio, DM. "Lipid loading alters metabolic function of primary human adipocytes grown in culture." June 2007.
Source
wos-lite
Published In
Diabetes
Volume
56
Publish Date
2007
Start Page
A359
End Page
A359

Carnitine revisited: potential use as adjunctive treatment in diabetes.

AIMS/HYPOTHESIS: This study examined the efficacy of supplemental L: -carnitine as an adjunctive diabetes therapy in mouse models of metabolic disease. We hypothesised that carnitine would facilitate fatty acid export from tissues in the form of acyl-carnitines, thereby alleviating lipid-induced insulin resistance. MATERIALS AND METHODS: Obese mice with genetic or diet-induced forms of insulin resistance were fed rodent chow +/- 0.5% L: -carnitine for a period of 1-8 weeks. Metabolic outcomes included insulin tolerance tests, indirect calorimetry and mass spectrometry-based profiling of acyl-carnitine esters in tissues and plasma. RESULTS: Carnitine supplementation improved insulin-stimulated glucose disposal in genetically diabetic mice and wild-type mice fed a high-fat diet, without altering body weight or food intake. In severely diabetic mice, carnitine supplementation increased average daily respiratory exchange ratio from 0.886 +/- 0.01 to 0.914 +/- 0.01 (p < 0.01), reflecting a marked increase in systemic carbohydrate oxidation. Similarly, under insulin-stimulated conditions, carbohydrate oxidation was higher and total energy expenditure increased from 172 +/- 10 to 210 +/- 9 kJ kg fat-free mass(-1) h(-1) in the carnitine-supplemented compared with control animals. These metabolic improvements corresponded with a 2.3-fold rise in circulating levels of acetyl-carnitine, which accounts for 86 and 88% of the total acyl-carnitine pool in plasma and skeletal muscle, respectively. Carnitine supplementation also increased several medium- and long-chain acyl-carnitine species in both plasma and tissues. CONCLUSIONS/INTERPRETATION: These findings suggest that carnitine supplementation relieves lipid overload and glucose intolerance in obese rodents by enhancing mitochondrial efflux of excess acyl groups from insulin-responsive tissues. Carefully controlled clinical trials should be considered.

Authors
Power, RA; Hulver, MW; Zhang, JY; Dubois, J; Marchand, RM; Ilkayeva, O; Muoio, DM; Mynatt, RL
MLA Citation
Power, RA, Hulver, MW, Zhang, JY, Dubois, J, Marchand, RM, Ilkayeva, O, Muoio, DM, and Mynatt, RL. "Carnitine revisited: potential use as adjunctive treatment in diabetes." Diabetologia 50.4 (April 2007): 824-832.
PMID
17310372
Source
pubmed
Published In
Diabetologia
Volume
50
Issue
4
Publish Date
2007
Start Page
824
End Page
832
DOI
10.1007/s00125-007-0605-4

Regulation of FAT/CD36 expression in human skeletal muscle

Authors
Bell, JA; Slentz, D; Muoio, DM; Dohm, GL
MLA Citation
Bell, JA, Slentz, D, Muoio, DM, and Dohm, GL. "Regulation of FAT/CD36 expression in human skeletal muscle." April 2007.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
21
Issue
6
Publish Date
2007
Start Page
A1302
End Page
A1302

Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism.

Acute exercise can reverse muscle insulin resistance, but the mechanism(s) of action are unknown. With the use of a hindlimb perfusion model, we have found that acute contraction restores insulin-stimulated glucose uptake in muscle of obese Zucker rats to levels witnessed in lean controls. Previous reports have suggested that obesity-related insulin resistance stems from lipid oversupply and tissue accumulation of toxic lipid intermediates that impair insulin signaling. We reasoned that contraction might activate hydrolysis and oxidation of intramuscular lipids, thus alleviating "lipotoxicity" and priming the muscle for enhanced insulin action. Indeed, analysis of mitochondrial-derived acyl-carnitine esters suggested that contraction caused robust increases in beta-oxidative flux and mitochondrial oxidation. As predicted, contraction decreased intramuscular triacylglycerol content; however, diacylglycerol and long chain acyl-CoAs, lipid intermediates presumed to trigger insulin resistance, were either unchanged or increased. In muscles from obese animals, insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 remained impaired after contraction, whereas phosphorylation of the downstream signaling protein, AS160, was partially restored. These results suggest that acute exercise enables diabetic muscle to circumvent upstream defects in insulin signal transduction via mechanisms that are more tightly coupled to increased mitochondrial energy metabolism than the lowering of diacylglycerol and long chain acyl-CoA.

Authors
Thyfault, JP; Cree, MG; Zheng, D; Zwetsloot, JJ; Tapscott, EB; Koves, TR; Ilkayeva, O; Wolfe, RR; Muoio, DM; Dohm, GL
MLA Citation
Thyfault, JP, Cree, MG, Zheng, D, Zwetsloot, JJ, Tapscott, EB, Koves, TR, Ilkayeva, O, Wolfe, RR, Muoio, DM, and Dohm, GL. "Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism." Am J Physiol Cell Physiol 292.2 (February 2007): C729-C739.
PMID
17050616
Source
pubmed
Published In
American journal of physiology. Cell physiology
Volume
292
Issue
2
Publish Date
2007
Start Page
C729
End Page
C739
DOI
10.1152/ajpcell.00311.2006

Lipid-induced metabolic dysfunction in skeletal muscle.

Insulin resistance is a hallmark of type 2 diabetes and commonly observed in other energy-stressed settings such as obesity, starvation, inactivity and ageing. Dyslipidaemia and 'lipotoxicity'--tissue accumulation of lipid metabolites-are increasingly recognized as important drivers of insulin resistant states. Mounting evidence suggests that lipid-induced metabolic dysfunction in skeletal muscle is mediated in large part by stress-activated serine kinases that interfere with insulin signal transduction. However, the metabolic and molecular events that connect lipid oversupply to stress kinase activation and glucose intolerance are as yet unclear. Application of transcriptomics and targeted mass spectrometry-based metabolomics tools has led to our finding that insulin resistance is a condition in which muscle mitochondria are persistently burdened with a heavy lipid load. As a result, high rates of beta-oxidation outpace metabolic flux through the TCA cycle, leading to accumulation of incompletely oxidized acyl-carnitine intermediates. In contrast, exercise training enhances mitochondrial performance, favouring tighter coupling between beta-oxidation and the TCA cycle, and concomitantly restores insulin sensitivity in animals fed a chronic high fat diet. The exercise-activated transcriptional co-activator, PGC1alpha, plays a key role in co-ordinating metabolic flux through these two intersecting metabolic pathways, and its suppression by overfeeding may contribute to obesity-associated mitochondrial dysfunction. Our emerging model predicts that muscle insulin resistance arises from mitochondrial lipid stress and a resultant disconnect between beta-oxidation and TCA cycle activity. Understanding this 'disconnect' and its molecular basis may lead to new therapeutic targets for combating metabolic disease.

Authors
Muoio, DM; Koves, TR
MLA Citation
Muoio, DM, and Koves, TR. "Lipid-induced metabolic dysfunction in skeletal muscle." Novartis Found Symp 286 (2007): 24-38.
PMID
18269172
Source
pubmed
Published In
Novartis Foundation Symposium
Volume
286
Publish Date
2007
Start Page
24
End Page
38

Discussion

Authors
Attie, AD; Spiegelman, BM; Bernlohr, DA; Shi, Y; Kim, JB; Glass, CK; O'Rahilly, S; Hotamisligil, GS; Li, P; Muoio, DM; Zhang, C-Y; Kadowaki, T
MLA Citation
Attie, AD, Spiegelman, BM, Bernlohr, DA, Shi, Y, Kim, JB, Glass, CK, O'Rahilly, S, Hotamisligil, GS, Li, P, Muoio, DM, Zhang, C-Y, and Kadowaki, T. "Discussion." Novartis Foundation Symposium 286 (2007): 6-12.
Source
scival
Published In
Novartis Foundation Symposium
Volume
286
Publish Date
2007
Start Page
6
End Page
12

Discussion

Authors
Spiegelman, BM; Muoio, DM; Black, PN; Hotamisligil, GS; Zhang, CY; Kadowaki, T; Bernlohr, DA; Shi, Y; Attie, AD
MLA Citation
Spiegelman, BM, Muoio, DM, Black, PN, Hotamisligil, GS, Zhang, CY, Kadowaki, T, Bernlohr, DA, Shi, Y, and Attie, AD. "Discussion." Novartis Foundation Symposium 286 (2007): 38-46.
Source
scival
Published In
Novartis Foundation Symposium
Volume
286
Publish Date
2007
Start Page
38
End Page
46

General discussion I

Authors
Saito, M; Spiegelman, BM; Glass, CK; O'Rahilly, S; Muoio, DM; Shi, Y
MLA Citation
Saito, M, Spiegelman, BM, Glass, CK, O'Rahilly, S, Muoio, DM, and Shi, Y. "General discussion I." Novartis Foundation Symposium 286 (2007): 162-163.
Source
scival
Published In
Novartis Foundation Symposium
Volume
286
Publish Date
2007
Start Page
162
End Page
163

Discussion

Authors
Attie, AD; Glass, CK; Spiegelman, BM; O'Rahilly, S; Tabas, I; Kim, JB; Bernlohr, DA; Muoio, DM
MLA Citation
Attie, AD, Glass, CK, Spiegelman, BM, O'Rahilly, S, Tabas, I, Kim, JB, Bernlohr, DA, and Muoio, DM. "Discussion." Novartis Foundation Symposium 286 (2007): 196-199.
Source
scival
Published In
Novartis Foundation Symposium
Volume
286
Publish Date
2007
Start Page
196
End Page
199

Discussion

Authors
Daum, G; Reue, K; Spiegelman, BM; Jae, BK; Yang, R; Muoio, DM; Tabas, I; Hotamisligil, GS; Shi, Y
MLA Citation
Daum, G, Reue, K, Spiegelman, BM, Jae, BK, Yang, R, Muoio, DM, Tabas, I, Hotamisligil, GS, and Shi, Y. "Discussion." Novartis Foundation Symposium 286 (2007): 68-71.
Source
scival
Published In
Novartis Foundation Symposium
Volume
286
Publish Date
2007
Start Page
68
End Page
71

Final discussion: Nutrition, ageing and lipotoxicity

Authors
Tabas, I; Black, PN; Spiegelman, BM; O'Rahilly, S; Bernlohr, DA; Glass, CK; Muoio, DM; Attie, AD
MLA Citation
Tabas, I, Black, PN, Spiegelman, BM, O'Rahilly, S, Bernlohr, DA, Glass, CK, Muoio, DM, and Attie, AD. "Final discussion: Nutrition, ageing and lipotoxicity." Novartis Foundation Symposium 286 (2007): 200-203.
Source
scival
Published In
Novartis Foundation Symposium
Volume
286
Publish Date
2007
Start Page
200
End Page
203

Discussion

Authors
Spiegelman, BM; Hotamisligil, GS; Attie, AD; O'Rahilly, S; Muoio, DM; Bernlohr, DA; Tabas, I; Shi, Y; Han, X
MLA Citation
Spiegelman, BM, Hotamisligil, GS, Attie, AD, O'Rahilly, S, Muoio, DM, Bernlohr, DA, Tabas, I, Shi, Y, and Han, X. "Discussion." Novartis Foundation Symposium 286 (2007): 94-98.
Source
scival
Published In
Novartis Foundation Symposium
Volume
286
Publish Date
2007
Start Page
94
End Page
98

Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs.

In the absence of specific high-affinity agonists and antagonists, it has been difficult to define the target genes and biological responses attributable to many of the orphan nuclear receptors (ONRs). Indeed, it appears that many members of this receptor superfamily are not regulated by classical small molecules but rather their activity is controlled by interacting cofactors. Motivated by this finding, we have developed an approach to genetically isolate specific receptor-cofactor pairs in cells, allowing us to define the biological responses attributable to each complex. This is accomplished by using combinatorial peptide phage display to engineer the receptor interacting domain of each cofactor such that it interacts selectively with one nuclear receptor. In this study, we describe the customization of PGC-1alpha and its use to study the biology of the estrogen-related receptor alpha (ERRalpha) in cultured liver cells.

Authors
Gaillard, S; Grasfeder, LL; Haeffele, CL; Lobenhofer, EK; Chu, T-M; Wolfinger, R; Kazmin, D; Koves, TR; Muoio, DM; Chang, C-Y; McDonnell, DP
MLA Citation
Gaillard, S, Grasfeder, LL, Haeffele, CL, Lobenhofer, EK, Chu, T-M, Wolfinger, R, Kazmin, D, Koves, TR, Muoio, DM, Chang, C-Y, and McDonnell, DP. "Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs." Mol Cell 24.5 (December 8, 2006): 797-803.
PMID
17157261
Source
pubmed
Published In
Molecular Cell
Volume
24
Issue
5
Publish Date
2006
Start Page
797
End Page
803
DOI
10.1016/j.molcel.2006.10.012

Obesity-related derangements in metabolic regulation.

An epidemic surge in the incidence of obesity has occurred worldwide over the past two decades. This alarming trend has been triggered by lifestyle habits that encourage overconsumption of energy-rich foods while also discouraging regular physical activity. These environmental influences create a chronic energy imbalance that leads to persistent weight gain in the form of body fat and a host of other abnormalities in metabolic homeostasis. As adiposity increases, so does the risk of developing comorbidities such as diabetes, hypertension, and cardiovascular disease. The intimate association between obesity and systemic metabolic dysregulation has inspired a new area of biochemistry research in which scientists are seeking to understand the molecular mechanisms that link chronic lipid oversupply to tissue dysfunction and disease development. The purpose of this chapter is to review recent findings in this area, placing emphasis on lipid-induced functional impairments in the major peripheral organs that control energy flux: adipose tissue, the liver, skeletal muscle, and the pancreas.

Authors
Muoio, DM; Newgard, CB
MLA Citation
Muoio, DM, and Newgard, CB. "Obesity-related derangements in metabolic regulation." Annu Rev Biochem 75 (2006): 367-401. (Review)
PMID
16756496
Source
pubmed
Published In
Annual Review of Biochemistry
Volume
75
Publish Date
2006
Start Page
367
End Page
401
DOI
10.1146/annurev.biochem.75.103004.142512

Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans.

Obesity and type 2 diabetes are strongly associated with abnormal lipid metabolism and accumulation of intramyocellular triacylglycerol, but the underlying cause of these perturbations are yet unknown. Herein, we show that the lipogenic gene, stearoyl-CoA desaturase 1 (SCD1), is robustly up-regulated in skeletal muscle from extremely obese humans. High expression and activity of SCD1, an enzyme that catalyzes the synthesis of monounsaturated fatty acids, corresponded with low rates of fatty acid oxidation, increased triacylglycerol synthesis and increased monounsaturation of muscle lipids. Elevated SCD1 expression and abnormal lipid partitioning were retained in primary skeletal myocytes derived from obese compared to lean donors, implying that these traits might be driven by epigenetic and/or heritable mechanisms. Overexpression of human SCD1 in myotubes from lean subjects was sufficient to mimic the obese phenotype. These results suggest that elevated expression of SCD1 in skeletal muscle contributes to abnormal lipid metabolism and progression of obesity.

Authors
Hulver, MW; Berggren, JR; Carper, MJ; Miyazaki, M; Ntambi, JM; Hoffman, EP; Thyfault, JP; Stevens, R; Dohm, GL; Houmard, JA; Muoio, DM
MLA Citation
Hulver, MW, Berggren, JR, Carper, MJ, Miyazaki, M, Ntambi, JM, Hoffman, EP, Thyfault, JP, Stevens, R, Dohm, GL, Houmard, JA, and Muoio, DM. "Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans." Cell Metab 2.4 (October 2005): 251-261.
PMID
16213227
Source
pubmed
Published In
Cell Metabolism
Volume
2
Issue
4
Publish Date
2005
Start Page
251
End Page
261
DOI
10.1016/j.cmet.2005.09.002

Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency.

Peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC1alpha) is a promiscuous co-activator that plays a key role in regulating mitochondrial biogenesis and fuel homeostasis. Emergent evidence links decreased skeletal muscle PGC1alpha activity and coincident impairments in mitochondrial performance to the development of insulin resistance in humans. Here we used rodent models to demonstrate that muscle mitochondrial efficiency is compromised by diet-induced obesity and is subsequently rescued by exercise training. Chronic high fat feeding caused accelerated rates of incomplete fatty acid oxidation and accumulation of beta-oxidative intermediates. The capacity of muscle mitochondria to fully oxidize a heavy influx of fatty acid depended on factors such as fiber type and exercise training and was positively correlated with expression levels of PGC1alpha. Likewise, an efficient lipid-induced substrate switch in cultured myocytes depended on adenovirus-mediated increases in PGC1alpha expression. Our results supported a novel paradigm in which a high lipid supply, occurring under conditions of low PGC1alpha, provokes a disconnect between mitochondrial beta-oxidation and tricarboxylic acid cycle activity. Conversely, the metabolic remodeling that occurred in response to PGC1alpha overexpression favored a shift from incomplete to complete beta-oxidation. We proposed that PGC1alpha enables muscle mitochondria to better cope with a high lipid load, possibly reflecting a fundamental metabolic benefit of exercise training.

Authors
Koves, TR; Li, P; An, J; Akimoto, T; Slentz, D; Ilkayeva, O; Dohm, GL; Yan, Z; Newgard, CB; Muoio, DM
MLA Citation
Koves, TR, Li, P, An, J, Akimoto, T, Slentz, D, Ilkayeva, O, Dohm, GL, Yan, Z, Newgard, CB, and Muoio, DM. "Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency." J Biol Chem 280.39 (September 30, 2005): 33588-33598.
PMID
16079133
Source
pubmed
Published In
The Journal of biological chemistry
Volume
280
Issue
39
Publish Date
2005
Start Page
33588
End Page
33598
DOI
10.1074/jbc.M507621200

Metabolism: A is for adipokine.

Authors
Muoio, DM; Newgard, CB
MLA Citation
Muoio, DM, and Newgard, CB. "Metabolism: A is for adipokine." Nature 436.7049 (July 21, 2005): 337-338.
PMID
16034406
Source
pubmed
Published In
Nature
Volume
436
Issue
7049
Publish Date
2005
Start Page
337
End Page
338
DOI
10.1038/436337a

Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential in liver for the metabolism of excess acyl-CoAs.

In vitro studies suggest that the mitochondrial glycerol-3-phosphate acyltransferase-1 (mtGPAT1) isoform catalyzes the initial and rate-controlling step in glycerolipid synthesis and aids in partitioning acyl-CoAs toward triacylglycerol synthesis and away from degradative pathways. To determine whether the absence of mtGPAT1 would increase oxidation of acyl-CoAs and restrict the development of hepatic steatosis, we fed wild type and mtGPAT1-/- mice a diet high in fat and sucrose (HH) for 4 months to induce the development of obesity and a fatty liver. Control mice were fed a diet low in fat and sucrose (LL). With the HH diet, absence of mtGPAT1 resulted in increased partitioning of acyl-CoAs toward oxidative pathways, demonstrated by 60% lower hepatic triacylglycerol content and 2-fold increases in plasma beta-hydroxybutyrate, acylcarnitines, and hepatic mRNA expression of mitochondrial HMG-CoA synthase. Despite the increase in fatty acid oxidation, liver acyl-CoA levels were 3-fold higher in the mtGPAT1-/- mice fed both diets. A lack of difference in CPT1 and FAS mRNA expression between genotypes suggested that the increased acyl-CoA content was not because of increased de novo synthesis, but instead, to an impaired ability to use long-chain acyl-CoAs derived from the diet, even when the dietary fat content was low. Hyperinsulinemia and reduced glucose tolerance on the HH diet was greater in the mtGPAT1-/- mice, which did not suppress the expression of the gluconeogenic genes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. This study demonstrates that mtGPAT1 is essential for normal acyl-CoA metabolism, and that the absence of hepatic mtGPAT1 results in the partitioning of fatty acids away from triacylglycerol synthesis and toward oxidation and ketogenesis.

Authors
Hammond, LE; Neschen, S; Romanelli, AJ; Cline, GW; Ilkayeva, OR; Shulman, GI; Muoio, DM; Coleman, RA
MLA Citation
Hammond, LE, Neschen, S, Romanelli, AJ, Cline, GW, Ilkayeva, OR, Shulman, GI, Muoio, DM, and Coleman, RA. "Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential in liver for the metabolism of excess acyl-CoAs." J Biol Chem 280.27 (July 8, 2005): 25629-25636.
PMID
15878874
Source
pubmed
Published In
The Journal of biological chemistry
Volume
280
Issue
27
Publish Date
2005
Start Page
25629
End Page
25636
DOI
10.1074/jbc.M503181200

Subsarcolemmal and intermyofibrillar mitochondria play distinct roles in regulating skeletal muscle fatty acid metabolism.

Skeletal muscle contains two populations of mitochondria that appear to be differentially affected by disease and exercise training. It remains unclear how these mitochondrial subpopulations contribute to fiber type-related and/or training-induced changes in fatty acid oxidation and regulation of carnitine palmitoyltransferase-1beta (CPT1beta), the enzyme that controls mitochondrial fatty acid uptake in skeletal muscle. To this end, we found that fatty acid oxidation rates were 8.9-fold higher in subsarcolemmal mitochondria (SS) and 5.3-fold higher in intermyofibrillar mitochondria (IMF) that were isolated from red gastrocnemius (RG) compared with white gastrocnemius (WG) muscle, respectively. Malonyl-CoA (10 muM), a potent inhibitor of CPT1beta, completely abolished fatty acid oxidation in SS and IMF mitochondria from WG, whereas oxidation rates in the corresponding fractions from RG were inhibited only 89% and 60%, respectively. Endurance training also elicited mitochondrial adaptations that resulted in enhanced fatty acid oxidation capacity. Ten weeks of treadmill running differentially increased palmitate oxidation rates 100% and 46% in SS and IMF mitochondria, respectively. In SS mitochondria, elevated fatty acid oxidation rates were accompanied by a 48% increase in citrate synthase activity but no change in CPT1 activity. Nonlinear regression analyses of mitochondrial fatty acid oxidation rates in the presence of 0-100 muM malonyl-CoA indicated that IC(50) values were neither dependent on mitochondrial subpopulation nor affected by exercise training. However, in IMF mitochondria, training reduced the Hill coefficient (P < 0.05), suggesting altered CPT1beta kinetics. These results demonstrate that endurance exercise provokes subpopulation-specific changes in mitochondrial function that are characterized by enhanced fatty acid oxidation and modified CPT1beta-malonyl-CoA dynamics.

Authors
Koves, TR; Noland, RC; Bates, AL; Henes, ST; Muoio, DM; Cortright, RN
MLA Citation
Koves, TR, Noland, RC, Bates, AL, Henes, ST, Muoio, DM, and Cortright, RN. "Subsarcolemmal and intermyofibrillar mitochondria play distinct roles in regulating skeletal muscle fatty acid metabolism." Am J Physiol Cell Physiol 288.5 (May 2005): C1074-C1082.
PMID
15647392
Source
pubmed
Published In
American journal of physiology. Cell physiology
Volume
288
Issue
5
Publish Date
2005
Start Page
C1074
End Page
C1082
DOI
10.1152/ajpcell.00391.2004

Glucose uptake in muscle cell cultures from endurance-trained men.

PURPOSE: To examine noninsulin- (basal) and insulin-mediated glucose uptake in human skeletal muscle cells from endurance-trained and sedentary individuals. METHODS: Muscle biopsies (vastus lateralis) were obtained from competitive, endurance-trained athletes (N=12; VO2peak 64.9+/-2.3 mL.kg-1.min-1) and their sedentary counterparts (N=8; VO2peak 51.8+/-2.2 mL.kg-1.min-1), and isolated satellite cells allowed to proceed to myotubes. RESULTS: The myotubes exhibited a dose response for glucose uptake with increasing insulin concentrations; maximal glucose uptake was approximately 1.5-fold over basal. In relation to exercise training status, basal glucose uptake was significantly (P<0.05) elevated by approximately 75% in the endurance-trained versus sedentary men (20.1+/-2.1 vs 11.9+/-1.9 pmol.mg protein-1.min-1, respectively). This difference persisted at insulin concentrations of 10 and 1000 etaM, although the relative increase in insulin-mediated glucose uptake (fold increase over basal) did not differ between the sedentary and endurance-trained cells. CONCLUSIONS: These data suggest that cultured skeletal muscle cells from endurance-trained athletes may differ in respect to basal glucose uptake.

Authors
Berggren, JR; Tanner, CJ; Koves, TR; Muoio, DM; Houmard, JA
MLA Citation
Berggren, JR, Tanner, CJ, Koves, TR, Muoio, DM, and Houmard, JA. "Glucose uptake in muscle cell cultures from endurance-trained men." Med Sci Sports Exerc 37.4 (April 2005): 579-584.
PMID
15809555
Source
pubmed
Published In
Medicine and Science in Sports and Exercise
Volume
37
Issue
4
Publish Date
2005
Start Page
579
End Page
584

Biomedicine. Insulin resistance takes a trip through the ER.

Authors
Muoio, DM; Newgard, CB
MLA Citation
Muoio, DM, and Newgard, CB. "Biomedicine. Insulin resistance takes a trip through the ER." Science 306.5695 (October 15, 2004): 425-426.
PMID
15486283
Source
pubmed
Published In
Science
Volume
306
Issue
5695
Publish Date
2004
Start Page
425
End Page
426
DOI
10.1126/science.1104680

Defects in morbidly obese skeletal muscle lipid metabolism are retained in primary cultures

Authors
Berggren, JR; Hulver, MW; Tanner, CL; Koves, T; Muoio, DM; Houmard, JA
MLA Citation
Berggren, JR, Hulver, MW, Tanner, CL, Koves, T, Muoio, DM, and Houmard, JA. "Defects in morbidly obese skeletal muscle lipid metabolism are retained in primary cultures." March 23, 2004.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
18
Issue
4
Publish Date
2004
Start Page
A689
End Page
A689

Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance.

Lipid infusion or ingestion of a high-fat diet results in insulin resistance, but the mechanism underlying this phenomenon remains unclear. Here we show that, in rats fed a high-fat diet, whole-animal, muscle and liver insulin resistance is ameliorated following hepatic overexpression of malonyl-coenzyme A (CoA) decarboxylase (MCD), an enzyme that affects lipid partitioning. MCD overexpression decreased circulating free fatty acid (FFA) and liver triglyceride content. In skeletal muscle, levels of triglyceride and long-chain acyl-CoA (LC-CoA)-two candidate mediators of insulin resistance-were either increased or unchanged. Metabolic profiling of 36 acylcarnitine species by tandem mass spectrometry revealed a unique decrease in the concentration of one lipid-derived metabolite, beta-OH-butyrate, in muscle of MCD-overexpressing animals. The best explanation for our findings is that hepatic expression of MCD lowered circulating FFA levels, which led to lowering of muscle beta-OH-butyrate levels and improvement of insulin sensitivity.

Authors
An, J; Muoio, DM; Shiota, M; Fujimoto, Y; Cline, GW; Shulman, GI; Koves, TR; Stevens, R; Millington, D; Newgard, CB
MLA Citation
An, J, Muoio, DM, Shiota, M, Fujimoto, Y, Cline, GW, Shulman, GI, Koves, TR, Stevens, R, Millington, D, and Newgard, CB. "Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance." Nat Med 10.3 (March 2004): 268-274.
PMID
14770177
Source
pubmed
Published In
Nature Medicine
Volume
10
Issue
3
Publish Date
2004
Start Page
268
End Page
274
DOI
10.1038/nm995

Peripheral metabolic actions of leptin.

The adipocyte-derived hormone, leptin, regulates food intake and systemic fuel metabolism; ob /ob mice, which lack functional leptin, exhibit an obesity syndrome that is similar to morbid obesity in humans. Leptin receptors are expressed most abundantly in the brain but are also present in several peripheral tissues. The role of leptin in controlling energy homeostasis has thus far focused on brain receptors and neuroendocrine pathways that regulate feeding behaviour and sympathetic nervous system activity. This chapter focuses on mounting evidence that leptin's effects on energy balance are also mediated by direct peripheral actions on key metabolic organs such as skeletal muscle, liver, pancreas and adipose tissue. Strong evidence indicates that peripheral leptin receptors regulate cellular lipid balance, favouring beta-oxidation over triacylglycerol storage. There are data to indicate that peripheral leptin also modulates glucose metabolism and insulin action; however, its precise role in controlling gluco-regulatory pathways remains uncertain and requires further investigation.

Authors
Muoio, DM; Lynis Dohm, G
MLA Citation
Muoio, DM, and Lynis Dohm, G. "Peripheral metabolic actions of leptin." Best Pract Res Clin Endocrinol Metab 16.4 (December 2002): 653-666. (Review)
PMID
12468413
Source
pubmed
Published In
Best Practice & Research: Clinical Endocrinology & Metabolism
Volume
16
Issue
4
Publish Date
2002
Start Page
653
End Page
666

Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta.

Ablation of peroxisome proliferator activated receptor (PPAR) alpha, a lipid-activated transcription factor that regulates expression of beta-oxidative genes, results in profound metabolic abnormalities in liver and heart. In the present study we used PPAR alpha knockout (KO) mice to determine whether this transcription factor is essential for regulating fuel metabolism in skeletal muscle. When animals were challenged with exhaustive exercise or starvation, KO mice exhibited lower serum levels of glucose, lactate, and ketones and higher nonesterified fatty acids than wild type (WT) littermates. During exercise, KO mice exhausted earlier than WT and exhibited greater rates of glycogen depletion in liver but not skeletal muscle. Fatty acid oxidative capacity was similar between muscles of WT and KO when animals were fed and only 28% lower in KO muscles when animals were starved. Exercise-induced regulation and starvation-induced regulation of pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, two classical and robustly responsive PPAR alpha target genes, were similar between WT and KO in skeletal muscle but markedly different between genotypes in heart. Real time quantitative PCR analyses showed that unlike in liver and heart, in mouse skeletal muscle PPAR delta is severalfold more abundant than either PPAR alpha or PPAR gamma. In both human and rodent myocytes, the highly selective PPAR delta agonist GW742 increased fatty acid oxidation about 2-fold and induced expression of several lipid regulatory genes, including pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, responses that were similar to those elicited by the PPAR alpha agonist GW647. These results show redundancy in the functions of PPARs alpha and delta as transcriptional regulators of fatty acid homeostasis and suggest that in skeletal muscle high levels of the delta-subtype can compensate for deficiency of PPAR alpha.

Authors
Muoio, DM; MacLean, PS; Lang, DB; Li, S; Houmard, JA; Way, JM; Winegar, DA; Corton, JC; Dohm, GL; Kraus, WE
MLA Citation
Muoio, DM, MacLean, PS, Lang, DB, Li, S, Houmard, JA, Way, JM, Winegar, DA, Corton, JC, Dohm, GL, and Kraus, WE. "Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta." J Biol Chem 277.29 (July 19, 2002): 26089-26097.
PMID
12118038
Source
pubmed
Published In
The Journal of biological chemistry
Volume
277
Issue
29
Publish Date
2002
Start Page
26089
End Page
26097
DOI
10.1074/jbc.M203997200

Evidence of a malonyl-CoA-insensitive carnitine palmitoyltransferase I activity in red skeletal muscle.

Carnitine palmitoyltransferase I (CPT I), which is expressed as two distinct isoforms in liver (alpha) and muscle (beta), catalyzes the rate-limiting step in the transport of fatty acid into the mitochondria. Malonyl-CoA, a potent inhibitor of CPT I, is considered a key regulator of fatty acid oxidation in both tissues. Still unanswered is how muscle beta-oxidation proceeds despite malonyl-CoA concentrations that exceed the IC(50) for CPT Ibeta. We evaluated malonyl-CoA-suppressible [(14)C]palmitate oxidation and CPT I activity in homogenates of red (RG) and white (WG) gastrocnemius, soleus (SOL), and extensor digitorum longus (EDL) muscles. Adding 10 microM malonyl-CoA inhibited palmitate oxidation by 29, 39, 60, and 89% in RG, SOL, EDL, and WG, respectively. Thus malonyl-CoA resistance, which correlated strongly (0.678) with absolute oxidation rates (RG > SOL > EDL > WG), was greater in red than in white muscles. Similarly, malonyl-CoA-resistant palmitate oxidation and CPT I activity were greater in mitochondria from RG compared with WG. Ribonuclease protection assays were performed to evaluate whether our data might be explained by differential expression of CPT I splice variants. We detected the presence of two CPT Ibeta splice variants that were more abundant in red compared with white muscle, but the relative expression of the two mRNA species was unrelated to malonyl-CoA resistance. These results provide evidence of a malonyl-CoA-insensitive CPT I activity in red muscle, suggesting fiber type-specific expression of distinct CPT I isoforms and/or posttranslational modulations that have yet to be elucidated.

Authors
Kim, J-Y; Koves, TR; Yu, G-S; Gulick, T; Cortright, RN; Dohm, GL; Muoio, DM
MLA Citation
Kim, J-Y, Koves, TR, Yu, G-S, Gulick, T, Cortright, RN, Dohm, GL, and Muoio, DM. "Evidence of a malonyl-CoA-insensitive carnitine palmitoyltransferase I activity in red skeletal muscle." Am J Physiol Endocrinol Metab 282.5 (May 2002): E1014-E1022.
PMID
11934665
Source
pubmed
Published In
American journal of physiology. Endocrinology and metabolism
Volume
282
Issue
5
Publish Date
2002
Start Page
E1014
End Page
E1022
DOI
10.1152/ajpendo.00233.2001

Peroxisome proliferator-activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cells.

In humans, skeletal muscle is a major site of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) expression, but its function in this tissue is unclear. We investigated the role of hPPAR-alpha in regulating muscle lipid utilization by studying the effects of a highly selective PPAR-alpha agonist, GW7647, on [(14)C]oleate metabolism and gene expression in primary human skeletal muscle cells. Robust induction of PPAR-alpha protein expression occurred during muscle cell differentiation and corresponded with differentiation-dependent increases in oleate oxidation. In mature myotubes, 48-h treatment with 10-1,000 nmol/l GW7647 increased oleate oxidation dose-dependently, up to threefold. Additionally, GW7647 decreased oleate esterification into myotube triacylglycerol (TAG), up to 45%. This effect was not abolished by etomoxir, a potent inhibitor of beta-oxidation, indicating that PPAR-alpha-mediated TAG depletion does not depend on reciprocal changes in fatty acid catabolism. Consistent with its metabolic actions, GW7647 induced mRNA expression of mitochondrial enzymes that promote fatty acid catabolism; carnitine palmityltransferase 1 and malonyl-CoA decarboxylase increased approximately 2-fold, whereas pyruvate dehydrogenase kinase 4 increased 45-fold. Expression of several genes that regulate glycerolipid synthesis was not changed by GW7647 treatment, implicating involvement of other targets to explain the TAG-depleting effect of the compound. These results demonstrate a role for hPPAR-alpha in regulating muscle lipid homeostasis.

Authors
Muoio, DM; Way, JM; Tanner, CJ; Winegar, DA; Kliewer, SA; Houmard, JA; Kraus, WE; Dohm, GL
MLA Citation
Muoio, DM, Way, JM, Tanner, CJ, Winegar, DA, Kliewer, SA, Houmard, JA, Kraus, WE, and Dohm, GL. "Peroxisome proliferator-activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cells." Diabetes 51.4 (April 2002): 901-909.
PMID
11916905
Source
pubmed
Published In
Diabetes
Volume
51
Issue
4
Publish Date
2002
Start Page
901
End Page
909

Evidence of a malonyl-CoA-insensitive carnitine palmitoyltransferase I activity in red skeletal muscle

Carnitine palmitoyltransferase I (CPT I), which is expressed as two distinct isoforms in liver (α) and muscle (β), catalyzes the rate-limiting step in the transport of fatty acid into the mitochondria. Malonyl-CoA, a potent inhibitor of CPT I, is considered a key regulator of fatty β-acid oxidation in both tissues. Still unanswered is how muscle oxidation proceeds despite malonyl-CoA concentrations that exceed the IC50 for CPT Iβ. We evaluated malonyl-CoA-suppressible [14C]palmitate oxidation and CPT I activity in homogenates of red (RG) and white (WG) gastrocnemius, soleus (SOL), and extensor digitorum longus (EDL) muscles. Adding 10 μM malonyl-CoA inhibited palmitate oxidation by 29, 39, 60, and 89% in RG, SOL, EDL, and WG, respectively. Thus malonyl-CoA resistance, which correlated strongly (0.678) with absolute oxidation rates (RG > SOL > EDL > WG), was greater in red than in white muscles. Similarly, malonyl-CoA-resistant palmitate oxidation and CPT I activity were greater in mitochondria from RG compared with WG. Ribonuclease protection assays were performed to evaluate whether our data might be explained by differential expression of CPT I splice variants. We detected the presence of two CPT Iβ splice variants that were more abundant in red compared with white muscle, but the relative expression of the two mRNA species was unrelated to malonyl-CoA resistance. These results provide evidence of a malonyl-CoA-insensitive CPT I activity in red muscle, suggesting fiber type-specific expression of distinct CPT I isoforms and/or posttranslational modulations that have yet to be elucidated.

Authors
Kim, J-Y; Koves, TR; Yu, G-S; Gulick, T; Cortright, RN; Dohm, GL; Muoio, DM
MLA Citation
Kim, J-Y, Koves, TR, Yu, G-S, Gulick, T, Cortright, RN, Dohm, GL, and Muoio, DM. "Evidence of a malonyl-CoA-insensitive carnitine palmitoyltransferase I activity in red skeletal muscle." American Journal of Physiology - Endocrinology and Metabolism 282.5 45-5 (2002): E1014-E1022.
Source
scival
Published In
American journal of physiology. Endocrinology and metabolism
Volume
282
Issue
5 45-5
Publish Date
2002
Start Page
E1014
End Page
E1022

Acyl-CoAs are functionally channeled in liver: potential role of acyl-CoA synthetase.

Acyl-CoA synthetase (ACS) catalyzes the activation of long-chain fatty acids to acyl-CoAs, which can be metabolized to form CO(2), triacylglycerol (TAG), phospholipids (PL), and cholesteryl esters (CE). To determine whether inhibiting ACS affects these pathways differently, we incubated rat hepatocytes with [(14)C]oleate and the ACS inhibitor triacsin C. Triacsin inhibited TAG synthesis 70% in hepatocytes from fed rats and 40% in starved rats, but it had little effect on oleate incorporation into CE, PL, or beta-oxidation end products. Triacsin blocked [(3)H]glycerol incorporation into TAG and PL 33 and 25% more than it blocked [(14)C]oleate incorporation, suggesting greater inhibition of de novo TAG synthesis than reacylation. Triacsin did not affect oxidation of prelabeled intracellular lipid. ACS1 protein was abundant in liver microsomes but virtually undetectable in mitochondria. Refeeding increased microsomal ACS1 protein 89% but did not affect specific activity. Triacsin inhibited ACS specific activity in microsomes more from fed than from starved rats. These data suggest that ACS isozymes may be functionally linked to specific metabolic pathways and that ACS1 is not associated with beta-oxidation in liver.

Authors
Muoio, DM; Lewin, TM; Wiedmer, P; Coleman, RA
MLA Citation
Muoio, DM, Lewin, TM, Wiedmer, P, and Coleman, RA. "Acyl-CoAs are functionally channeled in liver: potential role of acyl-CoA synthetase." Am J Physiol Endocrinol Metab 279.6 (December 2000): E1366-E1373.
PMID
11093925
Source
pubmed
Published In
American journal of physiology. Endocrinology and metabolism
Volume
279
Issue
6
Publish Date
2000
Start Page
E1366
End Page
E1373

Energy metabolism in uncoupling protein 3 gene knockout mice.

Uncoupling protein 3 (UCP3) is a member of the mitochondrial anion carrier superfamily. Based upon its high homology with UCP1 and its restricted tissue distribution to skeletal muscle and brown adipose tissue, UCP3 has been suggested to play important roles in regulating energy expenditure, body weight, and thermoregulation. Other postulated roles for UCP3 include regulation of fatty acid metabolism, adaptive responses to acute exercise and starvation, and prevention of reactive oxygen species (ROS) formation. To address these questions, we have generated mice lacking UCP3 (UCP3 knockout (KO) mice). Here, we provide evidence that skeletal muscle mitochondria lacking UCP3 are more coupled (i.e. increased state 3/state 4 ratio), indicating that UCP3 has uncoupling activity. In addition, production of ROS is increased in mitochondria lacking UCP3. This study demonstrates that UCP3 has uncoupling activity and that its absence may lead to increased production of ROS. Despite these effects on mitochondrial function, UCP3 does not seem to be required for body weight regulation, exercise tolerance, fatty acid oxidation, or cold-induced thermogenesis. The absence of such phenotypes in UCP3 KO mice could not be attributed to up-regulation of other UCP mRNAs. However, alternative compensatory mechanisms cannot be excluded. The consequence of increased mitochondrial coupling in UCP3 KO mice on metabolism and the possible role of yet unidentified compensatory mechanisms, remains to be determined.

Authors
Vidal-Puig, AJ; Grujic, D; Zhang, CY; Hagen, T; Boss, O; Ido, Y; Szczepanik, A; Wade, J; Mootha, V; Cortright, R; Muoio, DM; Lowell, BB
MLA Citation
Vidal-Puig, AJ, Grujic, D, Zhang, CY, Hagen, T, Boss, O, Ido, Y, Szczepanik, A, Wade, J, Mootha, V, Cortright, R, Muoio, DM, and Lowell, BB. "Energy metabolism in uncoupling protein 3 gene knockout mice." J Biol Chem 275.21 (May 26, 2000): 16258-16266.
PMID
10748196
Source
pubmed
Published In
The Journal of biological chemistry
Volume
275
Issue
21
Publish Date
2000
Start Page
16258
End Page
16266
DOI
10.1074/jbc.M910179199

Physiological and nutritional regulation of enzymes of triacylglycerol synthesis.

Although triacylglycerol stores play the critical role in an organism's ability to withstand fuel deprivation and are strongly associated with such disorders as diabetes, obesity, and atherosclerotic heart disease, information concerning the enzymes of triacylglycerol synthesis, their regulation by hormones, nutrients, and physiological conditions, their mechanisms of action, and the roles of specific isoforms has been limited by a lack of cloned cDNAs and purified proteins. Fortunately, molecular tools for several key enzymes in the synthetic pathway are becoming available. This review summarizes recent studies of these enzymes, their regulation under varying physiological conditions, their purported roles in synthesis of triacylglycerol and related glycerolipids, the possible functions of different isoenzymes, and the evidence for specialized cellular pools of triacylglycerol and glycerolipid intermediates.

Authors
Coleman, RA; Lewin, TM; Muoio, DM
MLA Citation
Coleman, RA, Lewin, TM, and Muoio, DM. "Physiological and nutritional regulation of enzymes of triacylglycerol synthesis." Annu Rev Nutr 20 (2000): 77-103. (Review)
PMID
10940327
Source
pubmed
Published In
Annual Review of Nutrition
Volume
20
Publish Date
2000
Start Page
77
End Page
103
DOI
10.1146/annurev.nutr.20.1.77

The effect of sex steroid hormones on substrate oxidation during prolonged submaximal exercise in women

In animals, female sex steroid hormones (SS, estrogens-progesterone) influence the energy substrate that is metabolized. Human research on this issue is controversial. This study examined whether changes in circulating SS hormone levels affected the carbohydrate-lipid metabolism during submaximal prolonged (60 min) exercise. Young, physically active females were studied. Four were classified as anovulatory-oligomenorrheic and four were classified as ovulatory-eumenorrheic. Subject responses were pooled to form one group (n=8) and then their responses under low (L) and high (H) pharmaceutically manipulated SS hormone conditions were examined. During exercise, the mean oxygen consumption levels were 1.70±0.10/· min-1 for L-SS and 1.75±0.11 /· min-1 for H-SS (p=0.07), respectively. The respiratory exchange ratio (RER) responses were significantly different during exercise between the conditions: 0.93±0.04 for L-SS and 0.90±0.04 for H-SS (p<0.05), respectively. RER responses were utilized to calculate substrate oxidation. Significantly less carbohydrate oxidation was found in the H-SS condition as compared to the L-SS condition (p<0.05). Lipid oxidation was also significantly different, but for this measure, the levels of oxidation were greater in the H-SS than in the L-SS condition (p<0.05). Finally, total energy expenditure for the 60 min of exercise was not significantly different between the hormonal conditions. Results suggest that sex steroid hormones have an impact upon substrate oxidation in women during exercise. Specifically, high circulating concentrations of the SS hormones result in an enhanced reliance upon the oxidation of lipid as an energy substrate and consequently induce a reduction in carbohydrate oxidation. The mechanism inducing this "metabolism shift" appears due to sex steroid hormones directly and indirectly increasing lipid mobilization and lipolysis.

Authors
Hackney, AC; Muoio, D; Meyer, WR
MLA Citation
Hackney, AC, Muoio, D, and Meyer, WR. "The effect of sex steroid hormones on substrate oxidation during prolonged submaximal exercise in women." Japanese Journal of Physiology 50.5 (2000): 489-494.
PMID
11120915
Source
scival
Published In
Japanese Journal of Physiology
Volume
50
Issue
5
Publish Date
2000
Start Page
489
End Page
494
DOI
10.2170/jjphysiol.50.489

Acyl-CoAs are functionally channeled in liver: Potential role of acyl-CoA synthetase

Acyl-CoA synthetase (ACS) catalyzes the activation of long-chain fatty acids to acyl-CoAs, which can be metabolized to form CO2, triacylglycerol (TAG), phospholipids (PL), and cholesteryl esters (CE). To determine whether inhibiting ACS affects these pathways differently, we incubated rat hepatocytes with [14C]oleate and the ACS inhibitor triacsin C. Triacsin inhibited TAG synthesis 70% in hepatocytes from fed rats and 40% in starved rats, but it had little effect on oleate incorporation into CE, PL, or β-oxidation end products. Triacsin blocked [3H]glycerol incorporation into TAG and PL 33 and 25% more than it blocked [14C]oleate incorporation, suggesting greater inhibition of de novo TAG synthesis than reacylation. Triacsin did not affect oxidation of prelabeled intracellular lipid. ACS1 protein was abundant in liver microsomes but virtually undetectable in mitochondria. Refeeding increased microsomal ACS1 protein 89% but did not affect specific activity. Triacsin inhibited ACS specific activity in microsomes more from fed than from starved rats. These data suggest that ACS isozymes may be functionally linked to specific metabolic pathways and that ACS1 is not associated with β-oxidation in liver.

Authors
Muoio, DM; Lewin, TM; Wiedmer, P; Coleman, RA
MLA Citation
Muoio, DM, Lewin, TM, Wiedmer, P, and Coleman, RA. "Acyl-CoAs are functionally channeled in liver: Potential role of acyl-CoA synthetase." American Journal of Physiology - Endocrinology and Metabolism 279.6 42-6 (2000): E1366-E1373.
Source
scival
Published In
American journal of physiology. Endocrinology and metabolism
Volume
279
Issue
6 42-6
Publish Date
2000
Start Page
E1366
End Page
E1373

Leptin opposes insulin's effects on fatty acid partitioning in muscles isolated from obese ob/ob mice.

Because muscle triacylglycerol (TAG) accumulation might contribute to insulin resistance in leptin-deficient ob/ob mice, we studied the acute (60- to 90-min) effects of leptin and insulin on [14C]glucose and [14C]oleate metabolism in muscles isolated from lean and obese ob/ob mice. In ob/ob soleus, leptin decreased glycogen synthesis 36-46% (P < 0.05), increased oleate oxidation 26% (P < 0.05), decreased oleate incorporation into TAG 32% (P < 0.05), and decreased the oleate partitioning ratio (oleate partitioned into TAG/CO2) 44% (P < 0.05). Insulin decreased oleate oxidation 31% (P < 0.05), increased oleate incorporation into TAG 46% (P < 0.05), and increased the partitioning ratio 125% (P < 0.01). Adding leptin diminished insulin's antioxidative, lipogenic effects. In soleus from lean mice, insulin increased the partitioning ratio 142%, whereas leptin decreased it 51%, as previously reported (Muoio, D. M. , G. L. Dohm, F. T. Fiedorek, E. B. Tapscott, and R. A. Coleman. Diabetes 46: 1360-1363, 1997). The phosphatidylinositol 3-kinase inhibitor wortmannin blocked insulin's effects on lipid metabolism but only attenuated leptin's effects. Increasing glucose concentration from 5 to 10 mM did not affect TAG synthesis, suggesting that insulin-induced lipogenesis is independent of increased glucose uptake. These data indicate that leptin opposes insulin's promotion of TAG accumulation in lean and ob/ob muscles. Because acute leptin exposure does not correct insulin resistance in ob/ob muscles, in vivo improvements in glucose homeostasis appear to require other long-term factors, possibly TAG depletion.

Authors
Muoio, DM; Dohm, GL; Tapscott, EB; Coleman, RA
MLA Citation
Muoio, DM, Dohm, GL, Tapscott, EB, and Coleman, RA. "Leptin opposes insulin's effects on fatty acid partitioning in muscles isolated from obese ob/ob mice." Am J Physiol 276.5 Pt 1 (May 1999): E913-E921.
PMID
10329986
Source
pubmed
Published In
The American journal of physiology
Volume
276
Issue
5 Pt 1
Publish Date
1999
Start Page
E913
End Page
E921

Leptin opposes insulin's effects on fatty acid partitioning in muscles isolated from obese ob/ob mice

Authors
Muoio, DM; Dohm, GL; Tapscott, EB; Coleman, RA
MLA Citation
Muoio, DM, Dohm, GL, Tapscott, EB, and Coleman, RA. "Leptin opposes insulin's effects on fatty acid partitioning in muscles isolated from obese ob/ob mice." AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM 276.5 (May 1999): E913-E921.
Source
wos-lite
Published In
American journal of physiology. Endocrinology and metabolism
Volume
276
Issue
5
Publish Date
1999
Start Page
E913
End Page
E921

AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target.

AMP-activated kinase (AMPK) is activated in response to metabolic stresses that deplete cellular ATP, and in both liver and skeletal muscle, activated AMPK stimulates fatty acid oxidation. To determine whether AMPK might reciprocally regulate glycerolipid synthesis, we studied liver and skeletal-muscle lipid metabolism in the presence of 5-amino-4-imidazolecarboxamide (AICA) riboside, a cell-permeable compound whose phosphorylated metabolite activates AMPK. Adding AICA riboside to cultured rat hepatocytes for 3 h decreased [14C]oleate and [3H]glycerol incorporation into triacylglycerol (TAG) by 50% and 38% respectively, and decreased oleate labelling of diacylglycerol by 60%. In isolated mouse soleus, a highly oxidative muscle, incubation with AICA riboside for 90 min decreased [14C]oleate incorporation into TAG by 37% and increased 14CO2 production by 48%. When insulin was present, [14C]oleate oxidation was 49% lower and [14C]oleate incorporation into TAG was 62% higher than under basal conditions. AICA riboside blocked insulin's antioxidative and lipogenic effects, increasing fatty acid oxidation by 78% and decreasing labelled TAG 43%. Similar results on fatty acid oxidation and acylglycerol synthesis were observed in C2C12 myoblasts, and in differentiated C2C12 myotubes, AICA riboside also inhibited the hydrolysis of intracellular TAG. These data suggest that AICA riboside might inhibit sn-glycerol-3-phosphate acyltransferase (GPAT), which catalyses the committed step in the pathway of glycerolipid biosynthesis. Incubating rat hepatocytes with AICA riboside for both 15 and 30 min decreased mitochondrial GPAT activity 22-34% without affecting microsomal GPAT, diacylglycerol acyltransferase or acyl-CoA synthetase activities. Finally, purified recombinant AMPKalpha1 and AMPKalpha2 inhibited hepatic mitochondrial GPAT in a time-and ATP-dependent manner. These data show that AMPK reciprocally regulates acyl-CoA channelling towards beta-oxidation and away from glycerolipid biosynthesis, and provide strong evidence that AMPK phosphorylates and inhibits mitochondrial GPAT.

Authors
Muoio, DM; Seefeld, K; Witters, LA; Coleman, RA
MLA Citation
Muoio, DM, Seefeld, K, Witters, LA, and Coleman, RA. "AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target." Biochem J 338 ( Pt 3) (March 15, 1999): 783-791.
PMID
10051453
Source
pubmed
Published In
The Biochemical journal
Volume
338 ( Pt 3)
Publish Date
1999
Start Page
783
End Page
791

Leptin opposes insulin's effects on fatty acid partitioning in muscles isolated from obese ob/ob mice

Because muscle triacylglycerol (TAG) accumulation might contribute to insulin resistance in leptin-deficient ob/ob mice, we studied the acute (60- to 90-min) effects of leptin and insulin on [14C]glucose and [14C]oleate metabolism in muscles isolated from lean and obese ob/ob mice. In ob/ob soleus, leptin decreased glycogen synthesis 36-46% (P < 0.05), increased oleate oxidation 26% (P < 0.05), decreased oleate incorporation into TAG 32% (P < 0.05), and decreased the oleate partitioning ratio (oleate partitioned into TAG/CO2) 44% (P < 0.05). Insulin decreased oleate oxidation 31% (P < 0.05), increased oleate incorporation into TAG 46% (P < 0.05), and increased the partitioning ratio 125% (P < 0.01). Adding leptin diminished insulin's antioxidative, lipogenic effects. In soleus from lean mice, insulin increased the partitioning ratio 142%, whereas leptin decreased it 51%, as previously reported (Muoio, D. M., G. L. Dohm, F. T. Fiedorek, E. B. Tapscott, and R. A. Coleman. Diabetes 46: 1360-1363, 1997). The phosphatidylinositol 3-kinase inhibitor wortmannin blocked insulin's effects on lipid metabolism but only attenuated leptin's effects. Increasing glucose concentration from 5 to 10 mM did not affect TAG synthesis, suggesting that insulin-induced lipogenesis is independent of increased glucose uptake. These data indicate that leptin opposes insulin's promotion of TAG accumulation in lean and ob/ob muscles. Because acute leptin exposure does not correct insulin resistance in ob/ob muscles, in vivo improvements in glucose homeostasis appear to require other long-term factors, possibly TAG depletion.

Authors
Muoio, DM; Dohm, GL; Tapscott, EB; Coleman, RA
MLA Citation
Muoio, DM, Dohm, GL, Tapscott, EB, and Coleman, RA. "Leptin opposes insulin's effects on fatty acid partitioning in muscles isolated from obese ob/ob mice." American Journal of Physiology - Endocrinology and Metabolism 276.5 39-5 (1999): E913-E921.
Source
scival
Published In
American journal of physiology. Endocrinology and metabolism
Volume
276
Issue
5 39-5
Publish Date
1999
Start Page
E913
End Page
E921

Evidence that acyl-CoAs are functionally channeled in liver

Activation of fatty acids by acyl-CoA synthetase (ACS) provides acyl-CoA for β-oxidation and for the synthesis of triacylglycerol (TAG), phospholipids (PL) and cholesterol esters (CE). Partitioning of acyl-CoAs towards these different metabolic fates is critical in the pathobiology of obesity, diabetes and hyperlipidemia. We used Triacsin C, a competitive inhibitor of long-chain ACS, to determine whether limited acyl-CoAs would be preferentially used for β-oxidation or complex lipid synthesis. Incubating cultured rat hepatocytes with 5 μM Triacsin for 24 hr decreased [14C]oleate incorporation into cellular TAG and CE by 76% and 26%, respectively (p<0.01), and acid soluble metabolites (ASM) (a measure of β-oxidation) by 42% (p<0.01), but did not affect incorporation into PL. Thus, acyl-CoAs were preferentially channeled into specific metabolic pathways. When cells were prelabeled for 24 hr with [14C]oleate, then chased for an additional 24 hr without label, Triacsin in the chase media did not inhibit labeling of ASM, indicating that Triacsin did not block oxidation of fatty acids hydrolyzed from endogenous acylglycerols. During 1 hr incubations, Triacsin decreased [14C]oleate incorporation into TAG by 36% (p<0.01), whereas it decreased [3H]glycerol incorporation into TAG by 58% (p<0.01), suggesting that Triacsin had a greater effect on de novo synthesis of TAG than on TAG synthesized from recycled acylglycerols. These data suggest that acyl-CoAs are actively channeled from targeted sources (exogenous compared to endogenous) towards specific metabolic pathways, possibly by multiple ACSs with distinct sensitivities to Triacsin.

Authors
Muoio, DM; Schmalz, P; Coleman, RA
MLA Citation
Muoio, DM, Schmalz, P, and Coleman, RA. "Evidence that acyl-CoAs are functionally channeled in liver." FASEB Journal 12.4 (1998): A229-.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
12
Issue
4
Publish Date
1998
Start Page
A229

Leptin directly alters partitioning in skeletal muscle (vol 46, pg 1360, 1997)

Authors
Muoio, DM; Dohm, GL; Fiedorek, FT; Tapscott, EB; Coleman, RA
MLA Citation
Muoio, DM, Dohm, GL, Fiedorek, FT, Tapscott, EB, and Coleman, RA. "Leptin directly alters partitioning in skeletal muscle (vol 46, pg 1360, 1997)." DIABETES 46.10 (October 1997): 1663-1663.
Source
wos-lite
Published In
Diabetes
Volume
46
Issue
10
Publish Date
1997
Start Page
1663
End Page
1663

Leptin directly alters lipid partitioning in skeletal muscle.

Leptin, an adipocyte-derived hormone that directly regulates both adiposity and energy homeostasis, decreases food intake and appears to partition metabolic fuels toward utilization and away from storage. Because skeletal muscle expresses the leptin receptor and plays a major role in determining energy metabolism, we studied leptin's effects on glucose and fatty acid (FA) metabolism in isolated mouse soleus and extensor digitorum longus (EDL) muscles. One muscle from each animal served as a basal control. The contralateral muscle was treated with insulin (10 mU/ml), leptin (0.01-10 microg/ml), or insulin plus leptin, and incorporation of [14C]glucose or [14C]oleate into CO2 and into either glycogen or triacylglycerol (TAG) was determined. Leptin increased soleus muscle FA oxidation by 42% (P < 0.001) and decreased incorporation of FA into TAG by 35% (P < 0.01) in a dose-dependent manner. In contrast, insulin decreased soleus muscle FA oxidation by 40% (P < 0.001) and increased incorporation into TAG by 70% (P < 0.001). When both hormones were present, leptin attenuated both the antioxidative and the lipogenic effects of insulin by 50%. Less pronounced hormone effects were observed in EDL muscle. Leptin did not alter insulin-stimulated muscle glucose metabolism. These data demonstrate that leptin has direct and acute effects on skeletal muscle.

Authors
Muoio, DM; Dohm, GL; Fiedorek, FT; Tapscott, EB; Coleman, RA
MLA Citation
Muoio, DM, Dohm, GL, Fiedorek, FT, Tapscott, EB, and Coleman, RA. "Leptin directly alters lipid partitioning in skeletal muscle." Diabetes 46.8 (August 1997): 1360-1363.
PMID
9231663
Source
pubmed
Published In
Diabetes
Volume
46
Issue
8
Publish Date
1997
Start Page
1360
End Page
1363

Leptin alters skeletal muscle lipid partitioning: Evidence for a direct role of leptin in a peripheral tissue.

Authors
Muoio, DM; Dohm, GL; Fiedorek, FT; Tapscott, EB; Coleman, RA
MLA Citation
Muoio, DM, Dohm, GL, Fiedorek, FT, Tapscott, EB, and Coleman, RA. "Leptin alters skeletal muscle lipid partitioning: Evidence for a direct role of leptin in a peripheral tissue." AMERICAN JOURNAL OF CLINICAL NUTRITION 66.1 (July 1997): 91-91.
Source
wos-lite
Published In
American Journal of Clinical Nutrition
Volume
66
Issue
1
Publish Date
1997
Start Page
91
End Page
91

Glucose-fatty acid substrate competition in isolated soleus muscle

Authors
Muoio, DM; Dohm, GL; Coleman, RA
MLA Citation
Muoio, DM, Dohm, GL, and Coleman, RA. "Glucose-fatty acid substrate competition in isolated soleus muscle." FASEB JOURNAL 11.3 (February 28, 1997): 2163-2163.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
11
Issue
3
Publish Date
1997
Start Page
2163
End Page
2163

Skeletal muscle lipid metabolism: A frontier for new insights into fuel homeostasis

Although skeletal muscle is recognized as a primary site of lipid utilization, the study of muscle bioenergetics has focused mainly on carbohydrate, and consequently our understanding of the variables that regulate muscle lipid metabolism is comparably poor. This review focuses on the significance of muscle lipid metabolism in regulating whole-body energy homeostasis. Multiple pathways involved in controlling muscle lipid biochemistry are discussed, and comparisons with other tissues are described. Considerable evidence indicates that muscle lipid biochemistry is altered in disease states, and a number of metabolic disorders may be explained by dysregulation of muscle lipid metabolism. An understanding of the factors accounting for dysregulated muscle metabolism is a necessity in light of the increase in the incidence of disease syndromes such as obesity and diabetes, which collectively account a high incidence of morbidity and mortality in the western society. Therefore, the purpose of this review is to describe the biochemical events involved in the regulation arid dysregulation skeletal muscle lipid metabolism and to encourage new investigation in muscle lipid research.

Authors
Cortright, RN; Muoio, DM; Dohm, GL
MLA Citation
Cortright, RN, Muoio, DM, and Dohm, GL. "Skeletal muscle lipid metabolism: A frontier for new insights into fuel homeostasis." Journal of Nutritional Biochemistry 8.5 (1997): 228-245.
Source
scival
Published In
Journal of Nutritional Biochemistry
Volume
8
Issue
5
Publish Date
1997
Start Page
228
End Page
245
DOI
10.1016/S0955-2863(97)89660-X

Glucose-fatty acid substrate competition in isolated soleus muscle

Obesity and NIDDM are associated with increased plasma free fatty acids (FFA), hyperinsulinemia and elevated muscle triacylglycerol (TAG). We investigated: 1) the role of elevated FFA as a direct inhibitor of muscle glucose metabolism, and 2) the effects of insulin and glucose on muscle lipid utilization Soleus muscle isolated from obese (ob/ob) mice and lean littermates were incubated for 90 minutes in Kreb's Ringer buffer (5.0 mM glucose) with 14C-glucose (1.0 μCi/ml) with and without 1.0 mM oleate; or with 0.5-1.5 mM 14C-oleate (1.0 μCi/ml). One muscle from each animal served as a basal control and the contralateral muscle was treated with insulin (10-7 M). Incorporation of label into CO2. and into either glycogen or TAG was determined. Obesity-associated insulin resistance was demonstrated by an 8 fold, compared to a 2-fold, insulin-stimulated increase in glycogen synthesis in muscle from lean and obese mice. respectively. Addition of oleate to the media did not affect either basal or insulin-stimulated glycogen synthesis, but oleate inhibited both basal and insulin-stimulated glucose oxidation by 40-50%. In the presence of both glucose and 14C-oleate. insulin increased TAG synthesis by 77% and 45% in muscle from lean compared to obese animals Basal oleate oxidation was similar in muscle from lean and obese mice, but insulin suppressed oleate oxidation by 44% and 20%, respectively. These data indicate: 1) that FFA selectively inhibits glucose oxidation but not glycogen synthesis. 2) that the degree of insulin resistance in muscle from obese animals differs for specific insulin-regulated glucose and lipid metabolic pathways, and 3) that insulin and glucose regulate muscle lipid partitioning by favoring lipid storage over oxidation. This suggests that hyperinsulinemic states suppress muscle FFA utilization and contribute to accumulation of muscle TAG.

Authors
Muoio, DM; Dohm, GL; Coleman, RA
MLA Citation
Muoio, DM, Dohm, GL, and Coleman, RA. "Glucose-fatty acid substrate competition in isolated soleus muscle." FASEB Journal 11.3 (1997): A373-.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
11
Issue
3
Publish Date
1997
Start Page
A373

Leptin directly alters lipid partitioning in skeletal muscle

Authors
MUOIO, D
MLA Citation
MUOIO, D. "Leptin directly alters lipid partitioning in skeletal muscle." Diabetes 46 (1997): 1360-1363.
Source
cinii-english
Published In
Diabetes
Volume
46
Publish Date
1997
Start Page
1360
End Page
1363
DOI
10.2337/diabetes.46.8.1360

Effect of dietary fat on metabolic adjustments to maximal VO2 and endurance in runners.

The present study examined the effects of dietary manipulations on six trained runners. The percent energy contributions from carbohydrate, fat, and protein were 61/24/14, 50/38/12, and 73/15/12 for the normal (N), fat (F), and carbohydrate (C) diets, respectively. Expiratory gases and blood responses to a maximum (VO2max) and a prolonged treadmill run were determined following 7 d on each diet. Free fatty acids (FFA), triglycerides, glycerol, glucose, and lactate were measured. Dietary assessment of subjects' N diet indicated that they were consuming approximately 700 kcal.d-1 less than estimated daily expenditures. Running time to exhaustion was greatest after the F diet (91.2 +/- 9.5 min, P < 0.05) as compared with the C (75.8 +/- 7.6 min, P < 0.05) and N (69.3 +/- 7.2 min, P < 0.05) diets. VO2max was also higher on the F diet (66.4 +/- 2.7 ml.kg-1 x min-1, P < 0.05) as compared with the C (59.6 +/- 2.8 ml.kg-1 x min-1, P < 0.05) and N (63.7 +/- 2.6 ml.kg-1 x min-1, P < 0.05) diets. Plasma FFA levels were higher (P < 0.05) and glycerol levels were lower (P < 0.05) during the F diet than during the C and N diets. Other biochemical measures did not differ significantly among diets. These data suggest that increased availability of FFA, consequent to the F diet, may provide for enhanced oxidative potential as evidenced by an increase in VO2max and running time. This implies that restriction of dietary fat may be detrimental to endurance performance.

Authors
Muoio, DM; Leddy, JJ; Horvath, PJ; Awad, AB; Pendergast, DR
MLA Citation
Muoio, DM, Leddy, JJ, Horvath, PJ, Awad, AB, and Pendergast, DR. "Effect of dietary fat on metabolic adjustments to maximal VO2 and endurance in runners." Med Sci Sports Exerc 26.1 (January 1994): 81-88.
PMID
8133743
Source
pubmed
Published In
Medicine and Science in Sports and Exercise
Volume
26
Issue
1
Publish Date
1994
Start Page
81
End Page
88
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