本期文章：《自然》：Online/在线发表

英国剑桥大学Stephen O’Rahilly、Anthony P. Coll等研究人员合作发现，GDF15介导二甲双胍对体重和能量平衡的影响。该研究于2019年12月25日在线发表于国际一流学术期刊《自然》。

在两项独立的随机对照临床试验中，研究人员发现二甲双胍可提高GDF15的循环水平（最近发现GDF15通过脑干限制性受体来减少食物摄入并降低体重）。在野生型小鼠中，口服二甲双胍可增加循环中的GDF15，而GDF15的表达主要在远端肠和肾脏中增加。在野生型小鼠中，二甲双胍阻止了对高脂饮食的体重增加，但在缺乏GDF15或其受体GFRAL的小鼠中却没有。

在肥胖、高脂饮食的小鼠中，二甲双胍减轻体重的作用被GFRAL拮抗剂抗体所逆转。二甲双胍对依赖GDF15的能量摄入和能量消耗都有影响。在没有GDF15作用的情况下，二甲双胍保持了降低循环葡萄糖水平的能力。总之，二甲双胍可提高GDF15的循环水平，这对于其对能量平衡和体重的有益作用是必需的，而GDF15作为其化学预防剂的主要贡献者。

据介绍，二甲双胍是世界上处方最广泛的抗糖尿病药物，也可有效预防高危人群中的2型糖尿病。60％以上的这种作用归功于二甲双胍持续降低体重的能力。二甲双胍降低体重的分子机制尚不清楚。

附：英文原文

Title: GDF15 mediates the effects of metformin on body weight and energy balance

Author: Anthony P. Coll, Michael Chen, Pranali Taskar, Debra Rimmington, Satish Patel, John Tadross, Irene Cimino, Ming Yang, Paul Welsh, Samuel Virtue, Deborah A. Goldspink, Emily L. Miedzybrodzka, Adam R. Konopka, Raul Ruiz Esponda, Jeffrey T-J. Huang, Y. C. Loraine Tung, Sergio Rodriguez-Cuenca, Rute A. Tomaz, Heather P. Harding, Audrey Melvin, Giles S. H. Yeo, David Preiss, Antonio Vidal-Puig, Ludovic Vallier, K. Sreekumaran Nair, Nicholas J. Wareham, David Ron, Fiona M. Gribble, Frank Reimann, Naveed Sattar, David B. Savage, Bernard B. Allan, Stephen ORahilly

Issue&Volume: 2019-12-25

Abstract: Metformin, the world’s most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. Over 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner3. The molecular mechanisms by which metformin lowers body weight are unknown. In two, independent randomised controlled clinical trials, circulating levels of GDF15, recently described to reduce food intake and lower body weight through a brain stem-restricted receptor, were increased by metformin. 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 GFRAL. In obese, high-fat-fed mice, 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 required GDF15. Metformin retained its ability to lower circulating glucose levels in the absence of GDF15 action. In summary, metformin elevates circulating levels of GDF15, which are necessary for its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.

DOI: 10.1038/s41586-019-1911-y

Source: https://www.nature.com/articles/s41586-019-1911-y

期刊信息

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：43.07
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