Soraphen, an inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet

Aim Inhibition of the acetyl-CoA carboxylase (ACC) system, consisting of the isozymes ACC1 and ACC2, may be beneficial for treatment of insulin resistance and/or obesity by interfering with de novo lipogenesis and beta-oxidation. We have evaluated effects of pharmacological inhibition of ACC by soraphen (SP) on high fat (HF) diet-induced insulin resistance in mice. Method Male C57Bl6/J mice were fed control chow, a HF diet or a HF diet supplemented with SP (50 or 100 mg/kg/day). Results Body weight gain and total body fat content of SP-treated animals were significantly reduced compared with HF-fed mice. Fractional synthesis of palmitate was significantly reduced in mice treated with SP, indicative for ACC1 inhibition. Plasma beta-hydroxybutyrate levels were significantly elevated by SP, reflecting simultaneous inhibition of ACC2 activity. Mice treated with SP showed improved peripheral insulin sensitivity, as assessed by hyperinsulinaemic euglycaemic clamps. Conclusion Pharmacological inhibition of the ACC system is of potential use for treatment of key components of the metabolic syndrome.