Interaction between metformin and leucine in reducing hyperlipidemia and hepatic lipid accumulation in diet-induced obese mice
Interaction between metformin and leucine in reducing hyperlipidemia and hepatic lipid accumulation in diet-induced obese mice
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DOI：
10.1016/j.metabol.2015.07.006
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发表时间：
2015-11-01
影响因子：
9.8
通讯作者：
Xue, Bingzhong
中科院分区：
文献类型：
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作者：
Fu, Lizhi;Bruckbauer, Antje;Xue, Bingzhong
背景亮氨酸在体外和体内刺激Sirt 1和AMPK信号传导。由于二甲双胍在相同的途径上收敛，我们在饮食诱导的肥胖胰岛素抵抗小鼠中测试了亮氨酸放大二甲双胍对AMPK介导的肝脏脂质代谢的影响的能力。给小鼠喂食高亮氨酸（24 g/kg饮食），含或不含亚治疗水平的二甲双胍（0.05-0.50 g/kg饮食）或治疗水平的二甲双胍（1.5 g/kg饮食;类似于300 mg/kg体重）。高脂饮食导致腹股沟脂肪垫重量增加10倍，肝脏重量增加25%，组织学证实为脂肪变性。亮氨酸-二甲双胍联合用药降低脂肪垫质量、正常化肝脏重量、肝脏和血浆脂质以及炎症标志物（白细胞介素6、白细胞介素1 β、肿瘤坏死因子α、单核细胞趋化蛋白-1、C反应蛋白）的效果与治疗性二甲双胍相当。此外，最高亚治疗水平的二甲双胍与亮氨酸产生的作用显著大于治疗水平的二甲双胍，并完全逆转了肝脂肪变性。这些作用是通过上调肝脏AMPK和肝脏脂肪生成基因（脂肪酸合成酶、硬脂酰CoA去饱和酶、乙酰CoA羧化酶）表达的相关变化介导的。低剂量亮氨酸-二甲双胍联合用药对肥胖的影响与治疗剂量的二甲双胍相当，并完全逆转饮食诱导肥胖小鼠的肝脂肪变性。(C)2015 Elsevier Inc. All rights reserved.
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.