GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand.
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| Abstract |
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.
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| Authors | 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 |
| Journal | Nature medicine (Nat Med) Vol. 23 Issue 10 Pg. 1158-1166 (Oct 2017) ISSN: 1546-170X [Electronic] United States |
| PMID | 28846099 (Publication Type: Journal Article) |
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