Abstract
Insulin resistance and type 2 diabetes are frequently accompanied by lipid accumulation in skeletal muscle. However, it is unknown whether primary lipid deposition in skeletal muscle is sufficient to cause insulin resistance or whether the type of muscle fiber, oxidative or glycolytic fiber, is an important determinant of lipid-mediated insulin resistance. Here we utilized transgenic mice to test the hypothesis that lipid accumulation specifically in glycolytic muscle promotes insulin resistance. Overexpression of DGAT2, which encodes an acyl-CoA:diacylglycerol acyltransferase that catalyzes triacylglycerol (TG) synthesis, in glycolytic muscle of mice increased the content of TG, ceramides, and unsaturated long-chain fatty acyl-CoAs in young adult mice. This lipid accumulation was accompanied by impaired insulin signaling and insulin-mediated glucose uptake in glycolytic muscle and impaired whole body glucose and insulin tolerance. We conclude that DGAT2-mediated lipid deposition specifically in glycolytic muscle promotes insulin resistance in this tissue and may contribute to the development of diabetes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acyl Coenzyme A / analysis
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Acyl Coenzyme A / metabolism
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Age Factors
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Animals
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Blood Glucose / metabolism
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Ceramides / analysis
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Ceramides / metabolism
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Diacylglycerol O-Acyltransferase / genetics*
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Diacylglycerol O-Acyltransferase / metabolism
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Diglycerides / analysis
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Diglycerides / metabolism
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Gene Expression / drug effects
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Glucose / metabolism
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Glucose Intolerance / blood
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Hypoglycemic Agents / pharmacology
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Insulin / pharmacology
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Insulin Resistance / genetics
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Insulin Resistance / physiology*
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Isoenzymes / metabolism
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Lipids / analysis*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Muscle Fibers, Fast-Twitch / chemistry
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Muscle Fibers, Fast-Twitch / drug effects
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Muscle Fibers, Fast-Twitch / metabolism*
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Muscle, Skeletal / chemistry
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Kinase C / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Triglycerides / analysis
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Triglycerides / metabolism
Substances
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Acyl Coenzyme A
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Blood Glucose
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Ceramides
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Diglycerides
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Hypoglycemic Agents
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Insulin
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Isoenzymes
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Lipids
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Triglycerides
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DGAT2 protein, human
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DGAT2 protein, mouse
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Diacylglycerol O-Acyltransferase
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Protein Kinase C
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Glucose