GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand

被引：499

作者：

Yang, Linda ^{[1
]}

Chang, Chih-Chuan ^{[1
]}

Sun, Zhe ^{[1
]}

Madsen, Dennis ^{[2
]}

Zhu, Haisun ^{[1
]}

Padkjaer, Soren B. ^{[2
]}

Wu, Xiaoai ^{[1
]}

Huang, Tao ^{[1
]}

Hultman, Karin ^{[2
]}

Paulsen, Sarah J. ^{[2
]}

Wang, Jishu ^{[1
]}

Bugge, Anne ^{[2
]}

Frantzen, Jane Boesen ^{[2
]}

Norgaard, Per ^{[2
]}

Jeppesen, Jacob Fuglsbjerg ^{[2
]}

Yang, Zhiru ^{[1
]}

Secher, Anna ^{[2
]}

Chen, Haibin ^{[1
]}

Li, Xun ^{[1
]}

John, Linu Mary ^{[2
]}

Shan, Bing ^{[1
]}

He, Zhenhua ^{[1
]}

Gao, Xiang ^{[1
]}

Su, Jing ^{[1
]}

Hansen, Kristian T. ^{[2
]}

Yang, Wei ^{[1
]}

Jorgensen, Sebastian Beck ^{[2
]}

机构：

[1] Novo Nordisk AS, Novo Nordisk Res Ctr China, Beijing, Peoples R China

[2] Novo Nordisk AS, Global Res, Malov, Denmark

来源：

NATURE MEDICINE | 2017年 / 23卷 / 10期

关键词：

TGF-BETA SUPERFAMILY; GDNF FAMILY LIGANDS; VAGAL AFFERENT; FOOD-INTAKE; MIC-1; RAT; RET; IDENTIFICATION; ACTIVATION; CYTOKINE;

D O I：

10.1038/nm.4394

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-beta 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 a-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.

引用

页码：1158 / +

页数：12

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