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

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 insulinstimulated 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 PKC 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. diet-induced obesity prevention ͉ intracellular diacylglycerol ͉ increased fat oxidation ͉ insulin resistance prevention

Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism

“…Consistent with our hypothesis of lipid metabolites inducing insulin resistance (6,9,10,(17)(18)(19)(20), muscle triglyceride, lysophosphatidic acid, and long-chain acyl CoAs were markedly increased in MPGC-1␣ TG mice fed a high-fat diet compared with WT mice (Fig. 3 A, C, and D).…”

Time-dependent effects of Prkce deletion on glucose homeostasis and hepatic lipid metabolism on dietary lipid oversupply in mice

“…This may prevent the build-up of ROS or products of incomplete β-oxidation, such as specific acylcarnitine esters, which have been linked to insulin resistance [33,34]. A reduction in β-oxidation in association with improved insulin sensitivity has been described predominantly in muscle [31,34] and is in direct contrast to other findings indicating a positive role for β-oxidation [35][36][37]. However, we now suggest the reduction we have observed may be beneficial in the liver under conditions of short-term lipid oversupply, especially as we observed a decrease in ROS generation in lipid-treated Prkce −/− hepatocytes.…”

OPINIONS Acetyl-coenzyme A carboxylase – an attractive enzyme for biotechnology

“…The method that enables versatile studies on ACCase genes functions in living organims relies on transgenic mouse lines with knock-out genes. A systemic ACC2 knock-out was reported to cause continuous fatty acids oxidation, reduced hepatic and body fat mass and an increase in energy expenditure, which was associated with reduced skeletal and cardiac muscle malonyl-coenzyme A and reduced susceptibility for diet-induced obesity and diabetes (Abu-Elheiga et al, 2001;Abu-Elheiga et al, 2003;Choi et al, 2007). Recently a new mouse line has been generated, which enabled conditional deletion of ACC2 gene from skeletal muscles -the predominant site of this gene expression.…”