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

Soo Choi Cheol, David B. Savage, Lutfi Abu-Elheiga, 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, Gerald I. Shulman

Research output: Contribution to journalArticle

231 Scopus citations

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 PKCθ activity in muscle and PKCε 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.

Original languageEnglish (US)
Pages (from-to)16480-16485
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number42
DOIs
StatePublished - Oct 16 2007

Keywords

  • Diet-induced obesity prevention
  • Increased fat oxidation
  • Insulin resistance prevention
  • Intracellular diacylglycerol

ASJC Scopus subject areas

  • General

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    Cheol, S. C., 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). 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(42), 16480-16485. https://doi.org/10.1073/pnas.0706794104