Interaction between metformin and leucine in reducing hyperlipidemia and hepatic lipid accumulation in diet-induced obese mice

Background. Leucine stimulates Sirt1 and AMPK signaling in vitro and in vivo. Since metformin converges on the same pathway, we have tested the ability of leucine to amplify the effects of metformin on AMPK-mediated hepatic lipid metabolism in diet-induced-obese insulin-resistant mice. Methods. Mice were fed high leucine (24 g/kg diet) with or without sub-therapeutic levels of metformin (0.05-0.50 g/kg diet) or therapeutic levels of metformin (1.5 g/kg diet; similar to 300 mg/kg body weight). Results. High-fat diet produced a 10-fold increase in inguinal fat pad weight and 25% increase in liver weight, histologically confirmed as steatosis. The leucine-metformin combinations reduced fat pad mass, normalized liver weight, liver and plasma lipids and inflammatory markers (interleukin 6, interleulcin 1 beta, tumor necrosis factor alpha, monocyte chemotactic protein-1, C-reactive protein) comparable to the effects of therapeutic metforrnin. Moreover, the highest sub-therapeutic levels of metformin with leucine exerted significantly greater effects than therapeutic levels of metformin and fully reversed hepatic steatosis. These effects were mediated by upregulation of hepatic AMPK and associated changes in lipogenic gene expression (fatty acid synthase, stearoyl CoA desaturase, acetyl CoA carboxylase) in the liver. Conclusion. A low-dose leucine-metformin combination exerts comparable effects on adiposity to therapeutic doses of metformin and fully reverses hepatic steatosis in dietinduced-obese mice. (C) 2015 Elsevier Inc. All rights reserved.