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

Autor: Per Nørgaard, Jing Su, Jane Boesen Frantzen, Zhiru Yang, Anne Bugge, Chih-Chuan Chang, Linu M. John, Anna Secher, Zhenhua He, Haisun Zhu, Tao Huang, Wei Yang, Kristian Tage Hansen, Xiaoai Wu, Xiang Gao, Sarah J Paulsen, Sebastian Beck Jørgensen, Jacob Jeppesen, Zhe Sun, Linda Yang, Haibin Chen, Bing Shan, Xun Li, Karin Hultman, Jishu Wang, Søren Berg Padkjær, Dennis Madsen
Rok vydání: 2017
Předmět:
Zdroj: Nature Medicine. 23:1158-1166
ISSN: 1546-170X
1078-8956
DOI: 10.1038/nm.4394
Popis: 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.
Databáze: OpenAIRE
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