The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL

被引：504

作者：

Emmerson, Paul J. ^{[1
]}

Wang, Feng ^{[2
]}

Du, Yong ^{[2
]}

Liu, Qian ^{[2
]}

Pickard, Richard T. ^{[1
]}

Gonciarz, Malgorzata D. ^{[1
]}

Coskun, Tamer ^{[1
]}

Hamang, Matthew J. ^{[1
]}

Sindelar, Dana K. ^{[1
]}

Ballman, Kimberly K. ^{[1
]}

Foltz, Lisa A. ^{[1
]}

Muppidi, Avinash ^{[1
]}

Alsina-Fernandez, Jorge ^{[1
]}

Barnard, Gavin C. ^{[1
]}

Tang, Jason X. ^{[1
]}

Liu, Xilin ^{[2
]}

Mao, Xudong ^{[2
]}

Siegel, Robert ^{[1
]}

Sloan, John H. ^{[1
]}

Mitchell, Pamela J. ^{[1
]}

Zhang, Bei B. ^{[2
]}

Gimeno, Ruth E. ^{[1
]}

Shan, Bei ^{[2
]}

Wu, Xinle ^{[2
]}

机构：

[1] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA

[2] Eli Lilly & Co, LCRDC, Shanghai, Peoples R China

来源：

NATURE MEDICINE | 2017年 / 23卷 / 10期

关键词：

TGF-BETA SUPERFAMILY; GDNF FAMILY; INHIBITORY CYTOKINE-1; EXPRESSION; BINDING; WEIGHT; AMYLIN; MIC-1; GENE;

D O I：

10.1038/nm.4393

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 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.

引用

页码：1215 / +

页数：7

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