Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity.

Authors: Choi CS; Savage DB; Abu-Elheiga L; Liu ZX; Kim S; Kulkarni A; Distefano A; Hwang YJ; Reznick RM; Codella R; Zhang D; Cline GW; Wakil SJ; Shulman GI

Abstract: 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.

Keywords: Acetyl-CoA Carboxylase/*genetics; Adipose Tissue/*enzymology; Animals; Cytokines/metabolism; Energy Metabolism/genetics; Glucose/metabolism; Insulin/*pharmacology; Insulin Resistance/*genetics; Isoenzymes/metabolism; Liver/enzymology; Mice; Mice, Knockout; Muscle, Skeletal/enzymology; Oxidation-Reduction; Protein Kinase C/metabolism; Protein Kinase C-epsilon/metabolism
Journal: Proceedings of the National Academy of Sciences of the United States of America
Volume: 104
Issue: 42
Pages: 16480-5
Date: Oct. 10, 2007
PMID: 17923673
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Citation:

Choi CS, Savage DB, Abu-Elheiga L, Liu ZX, Kim S, Kulkarni A, Distefano A, Hwang YJ, Reznick RM, Codella R, Zhang D, Cline GW, Wakil SJ, Shulman GI (2007) Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proceedings of the National Academy of Sciences of the United States of America 104: 16480-5.


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