Citations to this article
Citation Information: JCI Insight. 2018;3(3):e96805. https://doi.org/10.1172/jci.insight.96805.
Abstract
BACKGROUND. Accumulation of diacylglycerol (DAG) and sphingolipids is thought to promote skeletal muscle insulin resistance by altering cellular signaling specific to their location. However,the subcellular localization of bioactive lipids in human skeletal muscle is largely unknown. METHODS. We evaluated subcellular localization of skeletal muscle DAGs and sphingolipids in lean individuals (n = 15), endurance-trained athletes (n = 16), and obese men and women with (n = 12) and without type 2 diabetes (n = 15). Muscle biopsies were fractionated into sarcolemmal, cytosolic, mitochondrial/ER, and nuclear compartments. Lipids were measured using liquid chromatography tandem mass spectrometry, and insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp. RESULTS. Sarcolemmal 1,2-DAGs were not significantly related to insulin sensitivity. Sarcolemmal ceramides were inversely related to insulin sensitivity, with a significant relationship found for the C18:0 species. Sarcolemmal sphingomyelins were also inversely related to insulin sensitivity, with the strongest relationships found for the C18:1, C18:0, and C18:2 species. In the mitochondrial/ER and nuclear fractions, 1,2-DAGs were positively related to, while ceramides were inversely related to, insulin sensitivity. Cytosolic lipids as well as 1,3-DAG, dihydroceramides, and glucosylceramides in any compartment were not related to insulin sensitivity. All sphingolipids but only specific DAGs administered to isolated mitochondria decreased mitochondrial state 3 respiration. CONCLUSION. These data reveal previously unknown differences in subcellular localization of skeletal muscle DAGs and sphingolipids that relate to whole-body insulin sensitivity and mitochondrial function in humans. These data suggest that whole-cell concentrations of lipids obscure meaningful differences in compartmentalization and suggest that subcellular localization of lipids should be considered when developing therapeutic interventions to treat insulin resistance. FUNDING. National Institutes of Health General Clinical Research Center (RR-00036), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK089170), NIDDK (T32 DK07658), and Colorado Nutrition Obesity Research Center (P30DK048520).
Authors
Leigh Perreault, Sean A. Newsom, Allison Strauss, Anna Kerege, Darcy E. Kahn, Kathleen A. Harrison, Janet K. Snell-Bergeon, Travis Nemkov, Angelo D’Alessandro, Matthew R. Jackman, Paul S. MacLean, Bryan C. Bergman
Total citations by year
Citations to this article in year 2018 (7)
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Molecular Metabolism | 2018 |
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Distinct lipid droplet characteristics and distribution unmask the apparent contradiction of the athlete's paradox
S Daemen, A Gemmink, B Brouwers, RC Meex, PR Huntjens, G Schaart, E Moonen-Kornips, J Jörgensen, J Hoeks, P Schrauwen, MK Hesselink |
Molecular Metabolism | 2018 |
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Endocannabinoid Anandamide Mediates the Effect of Skeletal Muscle Sphingomyelins on Human Energy Expenditure
S Heinitz, A Basolo, D Piomelli, J Krakoff, P Piaggi |
The Journal of clinical endocrinology and metabolism | 2018 |
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Skeletal muscle ceramides and relationship with insulin sensitivity after 2 weeks of simulated sedentary behaviour and recovery in healthy older adults: Inactivity, insulin resistance and ceramide in ageing
PT Reidy, AI McKenzie, Z Mahmassani, VR Morrow, NM Yonemura, PN Hopkins, RL Marcus, MT Rondina, YK Lin, MJ Drummond |
The Journal of Physiology | 2018 |
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Insulin-stimulated Rac1-GTP binding is not impaired by palmitate treatment in L6 myotubes
HD Stierwalt, SE Ehrlicher, BC Bergman, MM Robinson, SA Newsom |
Physiological Reports | 2018 |
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Association Between Sphingolipids and Cardiopulmonary Fitness in Coronary Artery Disease Patients Undertaking Cardiac Rehabilitation
M Saleem, N Herrmann, A Dinoff, S Marzolini, MM Mielke, A Andreazza, PI Oh, SL Venkata, NJ Haughey, KL Lanctôt, DL Couteur |
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences | 2018 |
