Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant member of the transforming growth factor-β (TGF-β) superfamily and has been implicated in various biological functions, including cancer cachexia, renal and heart failure, atherosclerosis and metabolism. A connection between GDF15 and body-weight regulation was initially suggested on the basis of an observation that increasing GDF15 levels in serum correlated with weight loss in individuals with advanced prostate cancer. In animal models, overexpression of GDF15 leads to a lean phenotype, hypophagia and other improvements in metabolic parameters, suggesting that recombinant GDF15 protein could potentially be used in the treatment of obesity and type 2 diabetes. However, the signaling and mechanism of action of GDF15 are poorly understood owing to the absence of a clearly identified cognate receptor. Here we report that GDNF-family receptor α-like (GFRAL), an orphan member of the GFR-α family, is a high-affinity receptor for GDF15. GFRAL binds to GDF15 in vitro and is required for the metabolic actions of GDF15 with respect to body weight and food intake in vivo in mice. Gfral^-/- mice were refractory to the effects of recombinant human GDF15 on body-weight, food-intake and glucose parameters. Blocking the interaction between GDF15 and GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in rats. Gfral mRNA is highly expressed in the area postrema of mouse, rat and monkey, in accordance with previous reports implicating this region of the brain in the metabolic actions of GDF15 (refs. 4,5,6). Together, our data demonstrate that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15.

中文翻译：

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GDF15的代谢作用是由孤儿受体GFRAL介导的。

生长/分化因子15（GDF15），也称为MIC-1，是转化生长因子-β（TGF-β）超家族的遥远成员，与多种生物学功能有关，包括癌症恶病质，肾功能衰竭和心力衰竭，动脉粥样硬化和新陈代谢。最初的建议是，观察到血清中GDF15水平升高与晚期前列腺癌患者的体重减轻相关，这是GDF15与体重调节之间的联系。在动物模型中，GDF15的过度表达会导致瘦型，吞咽不足和其他代谢参数改善，这表明重组GDF15蛋白可以潜在地用于治疗肥胖症和2型糖尿病。然而，由于缺乏明确识别的同源受体，人们对GDF15的信号传导和作用机理了解甚少。在这里，我们报道GDNF-家族受体α-样（GFRAL），GFR-α家族的孤儿，是GDF15的高亲和力受体。GFRAL在体外与GDF15结合，是GDF15在小鼠体内相对于体重和食物摄入量的代谢作用所必需的。玻璃钢^-/-小鼠对重组人GDF15对体重，食物摄入和葡萄糖参数的影响具有抵抗力。用单克隆抗体阻断GDF15和GFRAL之间的相互作用可防止GDF15在大鼠中的代谢作用。根据先前的报道，大脑的这一区域参与了GDF15的代谢作用，Gfral mRNA在小鼠，大鼠和猴的后区域高表达（参考文献4,5,6）。总之，我们的数据表明GFRAL是GDF15的受体，介导GDF15的代谢作用。