Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-β superfamily and is associated with body-weight regulation in humans and rodents. However, the cognate receptor of GDF15 is unknown. Here we show that GDF15 binds specifically to GDNF family receptor α-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF15 stimulation. We also found that GDF15-mediated reductions in food intake and body weight of mice with obesity were abolished in GFRAL-knockout mice. We further found that GFRAL expression was limited to hindbrain neurons and not present in peripheral tissues, which suggests that GDF15-GFRAL-mediated regulation of food intake is by a central mechanism. Lastly, given that GDF15 did not increase energy expenditure in treated mice with obesity, the anti-obesity actions of the cytokine are likely driven primarily by a reduction in food intake.

中文翻译：

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GFRAL是GDF15的受体，是配体的抗肥胖作用所必需的。

生长分化因子15（GDF15；也称为MIC-1）是TGF-β超家族的不同成员，与人类和啮齿类动物的体重调节有关。但是，GDF15的同源受体是未知的。在这里，我们显示GDF15以高亲和力特异性结合GDNF家族受体α-样（GFRAL），并且GFRAL需要与共受体RET结合以响应GDF15刺激引起细胞内信号传导。我们还发现，在GFRAL敲除小鼠中，GDF15介导的肥胖症小鼠的食物摄入和体重减少减少了。我们进一步发现GFRAL的表达仅限于后脑神经元，并且在周围组织中不存在，这表明GDF15-GFRAL介导的食物摄取调节是由中心机制引起的。最后，