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

Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16480-5. doi: 10.1073/pnas.0706794104. Epub 2007 Oct 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Protein Kinase C-theta

Substances

  • Cytokines
  • Insulin
  • Isoenzymes
  • Prkcq protein, mouse
  • Protein Kinase C
  • Protein Kinase C-epsilon
  • Protein Kinase C-theta
  • Acacb protein, mouse
  • Acetyl-CoA Carboxylase
  • Glucose