高脂血症
二甲双胍
亮氨酸
医学
内分泌学
内科学
脂质积聚
药理学
糖尿病
化学
生物化学
氨基酸
作者
Lizhi Fu,Antje Bruckbauer,Fenfen Li,Qiang Cao,Xin Cui,Rui Wu,Hang Shi,Michael B. Zemel,Bingzhong Xue
标识
DOI:10.1016/j.metabol.2015.07.006
摘要
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.
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