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PNAS 104 (42): 16480-16485

Copyright © 2007 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

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

Cheol Soo Choi*, David B. Savage*, Lutfi Abu-Elheiga{dagger}, Zhen-Xiang Liu*, Sheene Kim*, Ameya Kulkarni*, Alberto Distefano*, Yu-Jin Hwang*, Richard M. Reznick*, Roberto Codella*, Dongyan Zhang*, Gary W. Cline*, Salih J. Wakil{dagger},{ddagger}, and Gerald I. Shulman*,§,¶,||

Departments of *Internal Medicine and §Cellular and Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and {dagger}Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030

Contributed by Salih J. Wakil, July 30, 2007 (sent for review June 1, 2007)

Received for publication June 1, 2007.

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{theta} activity in muscle and PKC{varepsilon} 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.

Key Words: diet-induced obesity prevention • intracellular diacylglycerol • increased fat oxidation • insulin resistance prevention

Author contributions: C.S.C. and D.B.S. contributed equally to this work; C.S.C., D.B.S., L.A.-E., S.J.W., and G.I.S. designed research; C.S.C., Z.-X.L., S.K., A.K., A.D., Y.-J.H., R.M.R., and D.Z. performed research; C.S.C., D.B.S., L.A.-E., Z.-X.L., S.K., A.K., A.D., Y.-J.H., R.M.R., R.C., D.Z., G.W.C., S.J.W., and G.I.S. analyzed data; and C.S.C., D.B.S., L.A.-E., Z.-X.L., S.K., A.K., A.D., Y.-J.H., R.M.R., R.C., D.Z., G.W.C., S.J.W., and G.I.S. wrote the paper.

The authors declare no conflict of interest.

{ddagger}To whom correspondence may be addressed. E-mail: swakil{at}bcm.tmc.edu

||To whom correspondence may be addressed at: Yale University School of Medicine, TAC S269, P.O. Box 9812, New Haven, CT 06536-8012. E-mail: gerald.shulman{at}yale.edu

© 2007 by The National Academy of Sciences of the USA

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