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Cited by 395Metabolism, Diabetes, and CancerAdipose Tissue and MetabolismLipid metabolism and biosynthesis

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Skeletal Muscle Triglycerides, Diacylglycerols, and Ceramides in Insulin Resistance

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Amati, Francesca, Dubé, John J., Alvarez-Carnero, Elvis, Edreira, Martin M., Chomentowski, Peter, Coen, Paul M., Switzer, Galen E., Bickel, Perry E., Stefanovic-Racic, Maja, Toledo, Frederico G.S., Goodpaster, Bret H.·2011·Diabetes
DOI 10.2337/db10-1221PMC PMC3178290
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Abstract

OBJECTIVE: Chronic exercise and obesity both increase intramyocellular triglycerides (IMTGs) despite having opposing effects on insulin sensitivity. We hypothesized that chronically exercise-trained muscle would be characterized by lower skeletal muscle diacylglycerols (DAGs) and ceramides despite higher IMTGs and would account for its higher insulin sensitivity. We also hypothesized that the expression of key skeletal muscle proteins involved in lipid droplet hydrolysis, DAG formation, and fatty-acid partitioning and oxidation would be associated with the lipotoxic phenotype. RESEARCH DESIGN AND METHODS: A total of 14 normal-weight, endurance-trained athletes (NWA group) and 7 normal-weight sedentary (NWS group) and 21 obese sedentary (OBS group) volunteers were studied. Insulin sensitivity was assessed by glucose clamps. IMTGs, DAGs, ceramides, and protein expression were measured in muscle biopsies. RESULTS: DAG content in the NWA group was approximately twofold higher than in the OBS group and ~50% higher than in the NWS group, corresponding to higher insulin sensitivity. While certain DAG moieties clearly were associated with better insulin sensitivity, other species were not. Ceramide content was higher in insulin-resistant obese muscle. The expression of OXPAT/perilipin-5, adipose triglyceride lipase, and stearoyl-CoA desaturase protein was higher in the NWA group, corresponding to a higher mitochondrial content, proportion of type 1 myocytes, IMTGs, DAGs, and insulin sensitivity. CONCLUSIONS: Total myocellular DAGs were markedly higher in highly trained athletes, corresponding with higher insulin sensitivity, and suggest a more complex role for DAGs in insulin action. Our data also provide additional evidence in humans linking ceramides to insulin resistance. Finally, this study provides novel evidence supporting a role for specific skeletal muscle proteins involved in intramyocellular lipids, mitochondrial oxidative capacity, and insulin resistance.

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FIG. 1. IMCLs and lipid droplet protein content in vastus lateralis. IMTG measured by the ORO stain (A) and lipid droplet volume density measured by electron microscopy (B). Bars are mean values and error bars are SEMs. The letters A and B above the bars denote significant differences between groups (P < 0.05, one-way ANOVA).
FIG. 1. IMCLs and lipid droplet protein content in vastus lateralis. IMTG measured by the ORO stain (A) and lipid droplet volume density measured by electron microscopy (B). Bars are mean values and error bars are SEMs. The letters A and B above the bars denote significant differences between groups (P < 0.05, one-way ANOVA).CC BY-NC-ND · PubMed Central
FIG. 2. DAGs in vastus lateralis. Total DAG content (A), saturated species (B), unsaturated species (C), and individual species (D). Bars are mean values, and error bars are SEMs. The letters A, B, and C above the bars denote significant differences between groups (P < 0.05, one-way ANOVA).
FIG. 2. DAGs in vastus lateralis. Total DAG content (A), saturated species (B), unsaturated species (C), and individual species (D). Bars are mean values, and error bars are SEMs. The letters A, B, and C above the bars denote significant differences between groups (P < 0.05, one-way ANOVA).CC BY-NC-ND · PubMed Central
FIG. 3. Ceramides and other sphingolipids in vastus lateralis. Total, saturated, and unsaturated ceramide content (A), sphingosine and S1P (B), and individual species of ceramides (C). Bars are mean rates, and error bars are SEMs. The letters A and B above the bars denote significant differences between groups (P < 0.05, one-way ANOVA).
FIG. 3. Ceramides and other sphingolipids in vastus lateralis. Total, saturated, and unsaturated ceramide content (A), sphingosine and S1P (B), and individual species of ceramides (C). Bars are mean rates, and error bars are SEMs. The letters A and B above the bars denote significant differences between groups (P < 0.05, one-way ANOVA).CC BY-NC-ND · PubMed Central
FIG. 4. Mitochondria and markers of oxidative capacity in vastus lateralis. Mitochondria volume density (A), example of micrographs (B), and SDH content (C). Bars are mean values, and error bars are SEMs. The letters A, B, and C above the bars denote significant differences between groups (P < 0.05, one-way ANOVA).
FIG. 4. Mitochondria and markers of oxidative capacity in vastus lateralis. Mitochondria volume density (A), example of micrographs (B), and SDH content (C). Bars are mean values, and error bars are SEMs. The letters A, B, and C above the bars denote significant differences between groups (P < 0.05, one-way ANOVA).CC BY-NC-ND · PubMed Central
FIG. 5. Lipid droplet protein content in vastus lateralis. Perilipin-5 (A), SCD1 (B), ATGL (C), and DGAT1 (D) protein contents measured by Western blotting. Bars are mean values, and error bars are SEMs. The letters A, B, and C above the bars denote significant differences between groups (P < 0.05, one-way ANOVA). The bands depicted in the Western blots are from one subject of each group.
FIG. 5. Lipid droplet protein content in vastus lateralis. Perilipin-5 (A), SCD1 (B), ATGL (C), and DGAT1 (D) protein contents measured by Western blotting. Bars are mean values, and error bars are SEMs. The letters A, B, and C above the bars denote significant differences between groups (P < 0.05, one-way ANOVA). The bands depicted in the Western blots are from one subject of each group.CC BY-NC-ND · PubMed Central

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Authors
Amati, F., Dubé, J. J., Alvarez-Carnero, E., Edreira, M. M., Chomentowski, P., Coen, P. M., Switzer, G. E., Bickel, P. E., Stefanovic-Racic, M., Toledo, F. G. S., & Goodpaster, B. H.
Affiliations
  • University of Pittsburgh (US)
  • Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
  • Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
  • Department of Medicine, Division of Endocrinology and Metabolism, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Corresponding author
Goodpaster, Bret H.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2011-09-16
Volume
60
Issue
10
Pages
2588-2597
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db10-1221
PMC
PMC3178290
OpenAlex
W2032345647
Cited by
395
References
54
Citations by year
2026: 13 · 2025: 18 · 2024: 13 · 2023: 17 · 2022: 18 · 2021: 16 · 2020: 28 · 2019: 27 · 2018: 38 · 2017: 32 · 2016: 41 · 2015: 41 · 2014: 29 · 2013: 35 · 2012: 27
FWCI
12.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • CONICET Digital (CONICET) (submittedVersion, cc-by-nc-sa)
  • SERVAL (Université de Lausanne) (submittedVersion, other-oa)
Funders
  • University of Pittsburgh (UL1RR024153, RR024153)
  • National Institutes of Health (5p30dk046204-15, RR024153, 1P30DK46204)
  • National Institute on Aging (R01 AG20128, P30AG024827)
  • National Institute of Diabetes and Digestive and Kidney Diseases (1P30DK-46204, R01DK068046, P30-DK046204)
  • National Center for Research Resources (RR-024153, UL1RR024153)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
insulin resistance, intramyocellular triglyceride, diacylglycerol, ceramide, endurance athletes, obesity, perilipin 5, adipose triglyceride lipase, stearoyl-CoA desaturase, mitochondrial oxidative capacity, fatty acid oxidation
MeSH terms
Aged, Ceramides, Diglycerides, Female, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Mitochondria, Muscle, Obesity, Oxygen Consumption, Physical Endurance, Triglycerides, Muscle, Skeletal, Athletes

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