Submitted on March 9, 2007
Accepted on September 27, 2007
Increased lipid accumulation and insulin resistance in transgenic mice expressing DGAT2 in glycolytic (type II) muscle
Malin C. Levin1, Mara Monetti1, Matthew J Watt2, Mini P. Sajan3, Robert D. Stevens4, James R. Bain5, Christopher B. Newgard6, Robert V. Farese3, and Robert V. Farese, Jr.1*
1 Gladstone Institute of Cardiovascular Disease, San Francisco, California, United States
2 Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
3 Department of Medicine, University of South Florida, James A. Haley Veterans Hospital, Tampa, Florida, United States
4 Stedman Metabolomics Laboratory, Stedman Nutrition and Metabolism Center, Durham, North Carolina, United States
5 Stedman Center Metabolomics Laboratory, Stedman Nutrition and Metabolism Center, Durham, North Carolina, United States
6 Stedman Nutrition and Metabolism Center, Durham, North Carolina, United States
* To whom correspondence should be addressed. E-mail: bfarese{at}gladstone.ucsf.edu.
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 fibers-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.
