Targeting Acetyl-CoA Carboxylase for Anti-obesity Therapy

Acetyl-CoA carboxylase catalyzes the first committed step in the synthesis of long-chain fatty acids. ACC has three domains each having a different function in the conversion of acetyl CoA to malonyl CoA. The activity of mammalian ACC is regulated by allosteric effectors and by covalent modification, including phosphorylation and dephosphorylation by various hormones. Also, the regulation of ACC by phosphorylation is considered to be a target for hypolipidemic agents. There are two mammalian isoforms of ACC and recent studies suggest that genetic or pharmacological manipulation of both the mitochondrial isoform and cytosolic isoforms of ACC may be effective antiobesity or anti-diabetic treatments. The importance of ACC as an anti-obesity agent are supported by many studies which demonstrate that modulation of fatty acid synthesis with an inhibitor of fatty acid synthase can reduce food intake, increase fatty acid oxidation, and result in rapid and profound weight loss. This review focuses on recent reports that identify a new ACC inhibitor and suggest strategies for the development of new ACC inhibitors. We also present evidence to suggest that inhibition of ACC in non-adipose cells could be important and discuss recent studies which indicate that modulation of ACC may be useful in the treatment of some types of cancer. In summary, the pharmacological manipulation of acetyl-CoA carboxylase could be a suitable target as an anti-obesity agent and current evidence also suggests that inhibition of ACC could be a useful therapeutic for the treatment of both diabetes and cancer.