GDF15 mediates the effects of metformin on body weight and energy balance
GDF15 mediates the effects of metformin on body weight and energy balance
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DOI：
10.1038/s41586-019-1911-y
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发表时间：
2019-12-25
期刊：
影响因子：
64.8
通讯作者：
O'Rahilly, Stephen
中科院分区：
文献类型：
--
作者：
Coll, Anthony P.;Chen, Michael;O'Rahilly, Stephen
在小鼠的研究中，二甲双胍治疗导致生长/分化因子15(GDF15)的分泌增加，GDF15可防止因高脂饮食而导致的体重增加，GDF15非依赖于循环血糖的降低。世界上最常用的抗糖尿病药物二甲双胍在高危人群中预防2型糖尿病也是有效的(1，2)。这种效果的60%以上可归因于二甲双胍持续减轻体重的能力(3)。二甲双胍降低体重的分子机制尚不清楚。在这里，我们在两个独立的随机对照临床试验中显示，二甲双胍增加了多肽激素生长/分化因子15(GDF15)的循环水平，该激素已被证明通过脑干限制性受体减少食物摄入量和减轻体重。在野生型小鼠中，口服二甲双胍增加了循环中的GDF15，GDF15的表达主要在远端肠道和肾脏增加。在野生型小鼠中，二甲双胍可以防止高脂饮食引起的体重增加，但在缺乏GDF15或其受体GDNF家族受体α样受体(GFRNAL)的小鼠中则不能。在高脂饮食的肥胖小鼠中，二甲双胍减轻体重的作用被GFFR拮抗剂抗体逆转。二甲双胍对依赖GDF15的能量摄入和能量消耗均有影响，但在缺乏GDF15活性的情况下仍有降低循环血糖水平的能力。综上所述，二甲双胍提高了循环中GDF15的水平，而GDF15是获得其对能量平衡和体重的有益影响所必需的，这是其作为化学预防性药物的主要贡献因素。
In mouse studies, metformin treatment results in increased secretion of growth/differentiation factor 15 (GDF15), which prevents weight gain in response to high-fat diet, and GDF15-independent lowering of circulating blood glucose.Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk(1,2). More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner(3). The molecular mechanisms by which metformin lowers body weight are unknown. Here we show-in two independent randomized controlled clinical trials-that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor alpha-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.