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GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand.
Nature Medicine ( IF 58.7 ) Pub Date : 2017-Oct-01 , DOI: 10.1038/nm.4394
Linda Yang , Chih-Chuan Chang , Zhe Sun , Dennis Madsen , Haisun Zhu , Søren B Padkjær , Xiaoai Wu , Tao Huang , Karin Hultman , Sarah J Paulsen , Jishu Wang , Anne Bugge , Jane Boesen Frantzen , Per Nørgaard , Jacob Fuglsbjerg Jeppesen , Zhiru Yang , Anna Secher , Haibin Chen , Xun Li , Linu Mary John , Bing Shan , Zhenhua He , Xiang Gao , Jing Su , Kristian T Hansen , Wei Yang , Sebastian Beck Jørgensen

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:

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,
更新日期:2017-09-07
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