The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL
The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL
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DOI：
10.1038/nm.4393
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发表时间：
2017-10-01
期刊：
影响因子：
82.9
通讯作者：
Wu, Xinle
中科院分区：
文献类型：
--
作者：
Emmerson, Paul J.;Wang, Feng;Wu, Xinle
生长/分化因子15（GDF 15），也称为MIC-1，是转化生长因子-β（TGF-β）超家族的远亲成员，并参与各种生物学功能，包括癌症恶病质、肾衰竭和心力衰竭、动脉粥样硬化和代谢（1）。GDF 15和体重调节之间的联系最初是基于血清中GDF 15水平增加与晚期前列腺癌患者体重减轻相关的观察而提出的（2）。在动物模型中，GDF 15的过表达导致瘦表型、食欲减退和代谢参数的其他改善（3），表明重组GDF 15蛋白可能用于治疗肥胖和2型糖尿病。然而，由于缺乏明确鉴定的同源受体，对GDF 15的信号传导和作用机制知之甚少。在这里，我们报告说，GDNF家族受体α样（GFRAL），GFR-α家族的孤儿成员，是一个高亲和力的受体GDF 15。GFRAL在体外与GDF 15结合，并且是GDF 15在小鼠体内关于体重和食物摄入的代谢作用所需的。Gfral（-/-）小鼠对重组人GDF 15对体重、食物摄入和葡萄糖参数的影响是难治的。用单克隆抗体阻断GDF 15和GFRAL之间的相互作用防止了GDF 15在大鼠中的代谢作用。Gfral mRNA在小鼠、大鼠和猴的最后区中高度表达，这与先前的报道一致，该报道暗示脑的该区域参与GDF 15的代谢作用（参考文献110）。（第4至6段）。总之，我们的数据表明GFRAL是GDF 15的受体，介导GDF 15的代谢作用。
Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant member of the transforming growth factor-beta (TGF-beta) superfamily and has been implicated in various biological functions, including cancer cachexia, renal and heart failure, atherosclerosis and metabolism(1). 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(2). In animal models, overexpression of GDF15 leads to a lean phenotype, hypophagia and other improvements in metabolic parameters(3), 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 alpha-like (GFRAL), an orphan member of the GFR-alpha 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. 4-6). Together, our data demonstrate that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15.