Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity.
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.
Choi
Cheol Soo
CS
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
Savage
David B
DB
Abu-Elheiga
Lutfi
L
Liu
Zhen-Xiang
ZX
Kim
Sheene
S
Kulkarni
Ameya
A
Distefano
Alberto
A
Hwang
Yu-Jin
YJ
Reznick
Richard M
RM
Codella
Roberto
R
Zhang
Dongyan
D
Cline
Gary W
GW
Wakil
Salih J
SJ
Shulman
Gerald I
GI
D000103:Acetyl-CoA Carboxylase / Q000235:genetics*; D000273:Adipose Tissue / Q000201:enzymology*; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000235:genetics*; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D000074121:Protein Kinase C-theta
D016207:Cytokines; D007328:Insulin; D007527:Isoenzymes; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D000074121:Protein Kinase C-theta; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase; D005947:Glucose