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

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

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Published in:	American journal of physiology: endocrinology and metabolism 2007-12, Vol.293 (6), p.E1772-E1781
Main Authors:	Levin, Malin C, Monetti, Mara, Watt, Matthew J, Sajan, Mini P, Stevens, Robert D, Bain, James R, Newgard, Christopher B, Farese, Robert V., Sr, Farese, Robert V., Jr
Format:	Article
Language:	eng
Subjects:	Acyl Coenzyme A - analysis Acyl Coenzyme A - metabolism Age Factors Animals Blood Glucose - metabolism Ceramides - analysis Ceramides - metabolism Diabetes Diacylglycerol O-Acyltransferase - genetics Diacylglycerol O-Acyltransferase - metabolism Diglycerides - analysis Diglycerides - metabolism Gene expression Gene Expression - drug effects Glucose Glucose - metabolism Glucose Intolerance - blood Hypoglycemic Agents - pharmacology Insulin Insulin - pharmacology Insulin Resistance - genetics Insulin Resistance - physiology Isoenzymes - metabolism Lipids Lipids - analysis Mice Mice, Inbred C57BL Mice, Transgenic Muscle Fibers, Fast-Twitch - chemistry Muscle Fibers, Fast-Twitch - drug effects Muscle Fibers, Fast-Twitch - metabolism Muscle, Skeletal - chemistry Muscle, Skeletal - drug effects Muscle, Skeletal - metabolism Musculoskeletal system Phosphatidylinositol 3-Kinases - metabolism Protein Kinase C - metabolism Proto-Oncogene Proteins c-akt - metabolism Rodents Triglycerides - analysis Triglycerides - metabolism
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Summary:	1 Gladstone Institute of Cardiovascular Disease, San Francisco, California; 2 St. Vincent's Institute of Medical Research, Fitzroy, Australia; 3 James A. Haley Veterans Hospital, Department of Medicine, University of South Florida, Tampa, Florida; 4 Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina; 5 Departments of Medicine and of Biochemistry and Biophysics; and 6 Diabetes 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 Address for reprint requests and other correspondence: R. V. Farese, Jr., Gladstone Institute of Cardiovascular Disease, 1650 Owens St., San Francisco, CA 94158 (e-mail: bfarese{at}gladstone.ucsf.edu )
ISSN:	0193-1849 1522-1555