Targeting Acetyl-CoA Carboxylase to Stay Lean

Science's STKE  23 Oct 2007:
Vol. 2007, Issue 409, pp. tw387
DOI: 10.1126/stke.4092007tw387

Acetyl-CoA carboxylase (ACC) regulates synthesis and oxidation of fatty acids, and mice lacking the ACC2 isoform are leaner than wild-type animals. Choi et al. further characterized whole-body energy metabolism and insulin sensitivity of Acc2–/– mice and obtained results supporting the possibility of ACC2 inhibitors as agents to treat obesity and type 2 diabetes. By monitoring activity of the animals, food consumption, and energy expenditure, the authors showed that Acc2–/– animals ate more food than did wild-type animals but were still leaner than the control animals. The Acc2–/– animals were also resistant to obesity brought on by eating a diet high in fats. These effects could be explained by the increase in energy expenditure that was observed in the knockout animals. Although oxidation of fats and of carbohydrates have been thought to be mutually exclusive (thus providing an explanation for insulin resistance observed in animals with excess fatty acids), Choi et al. found that oxidation of both fats and carbohydrates was increased in the Acc2–/– animals. Insulin responsiveness was also enhanced in the knockout animals. Resistance to insulin that occurs with fat accumulation is thought to result from accumulation of diacylglycerol in muscle and liver and consequent activation of protein kinase C (PKC) θ and PKCε in muscle and liver, respectively. In the Acc2–/– mice, enhanced sensitivity to insulin was associated with decreased activity of the PKC enzymes. ACC2 is not a particularly easy target for development of therapeutics in that the ACC1 isoform is required for viability during embryogenesis. Nevertheless, the authors propose, the properties of the Acc2–/– animals show that patients with common diseases like diabetes and obesity could be helped by continued efforts to develop a specific inhibitor for ACC2.

C. S. Choi, D. B. Savage, L. Abu-Elheiga, Z.-X. Liu, S. Kim, A. Kulkarni, A. Distefano, Y.-J. Hwang, R. M. Reznick, R. Codella, D. Zhang, G. W. Cline, S. J. Wakil, G. I. Shulman, 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. 104, 16480-16485 (2007). [Abstract] [Full Text]