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Increased lipid accumulation and insulin resistance in transgenic mice expressing DGAT2 in glycolytic (type II) muscle

¹Gladstone Institute of Cardiovascular Disease, San Francisco, California; ²St. Vincent's Institute of Medical Research, Fitzroy, Australia; ³James A. Haley Veterans Hospital, Department of Medicine, University of South Florida, Tampa, Florida; ⁴Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina; ⁵Departments of Medicine and of Biochemistry and Biophysics; and ⁶Diabetes Center, University of California, San Francisco, California

Submitted 9 March 2007 ; accepted in final form 27 September 2007

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.

acyl-CoA:diacylglycerol acyltransferase 2; skeletal muscle; glycolytic fibers; triacylglycerols

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