Lizhi Fu1, Antje Bruckbauer2, Fenfen Li1, Qiang Cao1, Xin Cui1, Rui Wu1, Hang Shi1, Michael B Zemel2, Bingzhong Xue3. 1. Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA. 2. NuSirt Biopharma Inc., 3835 Cleghorn Ave, Nashville, TN 37215, USA. 3. Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA. Electronic address: bxue@gsu.edu.
Abstract
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; ~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, interleukin 1 beta, tumor necrosis factor alpha, monocyte chemotactic protein-1, C-reactive protein) comparable to the effects of therapeutic metformin. 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 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; ~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, interleukin 1 beta, tumor necrosis factor alpha, monocyte chemotactic protein-1, C-reactive protein) comparable to the effects of therapeutic metformin. 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 diet-induced-obesemice.
Authors: N Chalasani; R Vuppalanchi; M Rinella; M S Middleton; M S Siddiqui; A S Barritt; O Kolterman; O Flores; C Alonso; M Iruarrizaga-Lejarreta; R Gil-Redondo; C B Sirlin; M B Zemel Journal: Aliment Pharmacol Ther Date: 2018-04-25 Impact factor: 8.171