31 Zhang, D. Liu, Z. X. Choi, C. S. Tian, L. Kibbey, R. Dong, J. Cline, G. W. Wood, P. A. Shulman, G. I. 2007 Proc Natl Acad Sci U S A 104 43 17075-80 Oct 23 0027-8424 (Print) 17940018 Triglycerides/biosynthesis Signal Transduction/drug effects Protein Kinase C-epsilon/metabolism Oxidation-Reduction/drug effects Muscle, Skeletal/drug effects/metabolism Mitochondria/drug effects/*enzymology/*pathology Mice Liver/*enzymology/metabolism/*pathology Insulin Resistance/*physiology Insulin/pharmacology Homeostasis/drug effects Glucose/metabolism Gene Expression Regulation/drug effects Fatty Liver/*enzymology/pathology Energy Metabolism/drug effects Diglycerides/biosynthesis Carbon Isotopes Calorimetry Animals Acyl-CoA Dehydrogenase, Long-Chain/*deficiency Acyl Coenzyme A/metabolism Muscle Skeletal/drug effects/metabolism Acyl-CoA Dehydrogenase Long-Chain/*deficiency Alterations in mitochondrial function have been implicated in the pathogenesis of insulin resistance and type 2 diabetes. However, it is unclear whether the reduced mitochondrial function is a primary or acquired defect in this process. To determine whether primary defects in mitochondrial beta-oxidation can cause insulin resistance, we studied mice with a deficiency of long-chain acyl-CoA dehydrogenase (LCAD), a key enzyme in mitochondrial fatty acid oxidation. Here, we show that LCAD knockout mice develop hepatic steatosis, which is associated with hepatic insulin resistance, as reflected by reduced insulin suppression of hepatic glucose production during a hyperinsulinemic-euglycemic clamp. The defects in insulin action were associated with an approximately 40% reduction in insulin-stimulated insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity and an approximately 50% decrease in Akt2 activation. These changes were associated with increased PKCepsilon activity and an aberrant 4-fold increase in diacylglycerol content after insulin stimulation. The increase in diacylglycerol concentration was found to be caused by de novo synthesis of diacylglycerol from medium-chain acyl-CoA after insulin stimulation. These data demonstrate that primary defects in mitochondrial fatty acid oxidation capacity can lead to diacylglycerol accumulation, PKCepsilon activation, and hepatic insulin resistance. R01 DK 40936/DK/NIDDK NIH HHS/United StatesR01 RR 02599/RR/NCRR NIH HHS/United StatesU24 DK 59635/DK/NIDDK NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tUnited States http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17940018