31 Choi, C. S. Savage, D. B. Abu-Elheiga, L. Liu, Z. X. Kim, S. Kulkarni, A. Distefano, A. Hwang, Y. J. Reznick, R. M. Codella, R. Zhang, D. Cline, G. W. Wakil, S. J. Shulman, G. I. 2007 Proc Natl Acad Sci U S A 104 42 16480-5 Oct 16 0027-8424 (Print) 17923673 Liver/enzymology Isoenzymes/metabolism Insulin Resistance/*genetics Insulin/*pharmacology Glucose/metabolism Energy Metabolism/genetics Cytokines/metabolism Animals Adipose Tissue/*enzymology Acetyl-CoA Carboxylase/*genetics Protein Kinase C-epsilon/metabolism Protein Kinase C/metabolism Oxidation-Reduction Muscle, Skeletal/enzymology Mice, Knockout Mice Muscle Knockout Skeletal/enzymology Acetyl-CoA carboxylase 2 (ACC)2 is a key regulator of mitochondrial fat oxidation. To examine the impact of ACC2 deletion on whole-body energy metabolism, we measured changes in substrate oxidation and total energy expenditure in Acc2(-/-) and WT control mice fed either regular or high-fat diets. To determine insulin action in vivo, we also measured whole-body insulin-stimulated liver and muscle glucose metabolism during a hyperinsulinemic-euglycemic clamp in Acc2(-/-) and WT control mice fed a high-fat diet. Contrary to previous studies that have suggested that increased fat oxidation might result in lower glucose oxidation, both fat and carbohydrate oxidation were simultaneously increased in Acc2(-/-) mice. This increase in both fat and carbohydrate oxidation resulted in an increase in total energy expenditure, reductions in fat and lean body mass and prevention from diet-induced obesity. Furthermore, Acc2(-/-) mice were protected from fat-induced peripheral and hepatic insulin resistance. These improvements in insulin-stimulated glucose metabolism were associated with reduced diacylglycerol content in muscle and liver, decreased PKC activity in muscle and PKCepsilon activity in liver, and increased insulin-stimulated Akt2 activity in these tissues. Taken together with previous work demonstrating that Acc2(-/-) mice have a normal lifespan, these data suggest that Acc2 inhibition is a viable therapeutic option for the treatment of obesity and type 2 diabetes. GM-63115/GM/NIGMS NIH HHS/United StatesP30 DK-45735/DK/NIDDK NIH HHS/United StatesR01 DK-40936/DK/NIDDK NIH HHS/United StatesU24 DK-76169/DK/NIDDK NIH HHS/United StatesWellcome Trust/United KingdomJournal 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=17923673