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

223 Citations (Scopus)

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
Externally publishedYes

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Acetyl-CoA Carboxylase
Knockout Mice
Energy Metabolism
Insulin Resistance
Fats
Insulin
Liver
High Fat Diet
Glucose
Muscles
Obesity
Carbohydrates
Glucose Clamp Technique
Diglycerides
Type 2 Diabetes Mellitus
Diet

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. / Cheol, Soo Choi; Savage, David B.; Abu-Elheiga, Lutfi; Liu, Zhen Xiang; Kim, Sheene; Kulkarni, Ameya; Distefano, Alberto; Hwang, Yu Jin; Reznick, Richard M.; Codella, Roberto; Zhang, Dongyan; Cline, Gary W.; Wakil, Salih J.; Shulman, Gerald I.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 42, 16.10.2007, p. 16480-16485.

Research output: Contribution to journalArticle

Cheol, SC, 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, vol. 104, no. 42, pp. 16480-16485. https://doi.org/10.1073/pnas.0706794104
Cheol, Soo Choi ; Savage, David B. ; Abu-Elheiga, Lutfi ; Liu, Zhen Xiang ; Kim, Sheene ; Kulkarni, Ameya ; Distefano, Alberto ; Hwang, Yu Jin ; Reznick, Richard M. ; Codella, Roberto ; Zhang, Dongyan ; Cline, Gary W. ; Wakil, Salih J. ; Shulman, Gerald I. / Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 42. pp. 16480-16485.
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