Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs. ^1,2,3). However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood^1,2,3. Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system⁴. Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15.

二甲双胍是 2 型糖尿病最常用的处方药，因为它具有降糖作用，这是通过抑制肝葡萄糖产生来介导的（参见参考文献^1、2、3）。然而，除了对肝脏的影响之外，二甲双胍还可以降低食欲，并且在临床前模型中，通过尚未完全了解的机制对衰老和许多不同的疾病（例如，认知障碍、癌症、心血管疾病）产生有益的影响^{1， 2,3}。鉴于肝脏中二甲双胍的高浓度及其许多超越血糖控制的有益作用，我们推断二甲双胍可能会增加与中枢神经系统相联系的肝细胞衍生内分泌因子的分泌⁴. 在这里，我们使用小鼠肝细胞的无偏转录组学和人血清中的蛋白质分析表明，二甲双胍诱导生长分化因子 15 (GDF15) 的表达和分泌。在原代小鼠肝细胞中，二甲双胍通过增加激活转录因子 4 (ATF4) 和 C/EBP 同源蛋白 (CHOP；也称为 DDIT3) 的表达来刺激 GDF15 的分泌。在喂食高脂肪饮食的野生型小鼠中，口服二甲双胍可增加血清 GDF15 并减少食物摄入、体重、空腹胰岛素和葡萄糖耐受不良；这些影响在 GDF15 缺失小鼠中被消除。血清 GDF15 的增加也与服用二甲双胍的 2 型糖尿病患者的体重减轻有关。