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

Nat Med. 2017 Oct;23(10):1158-1166. doi: 10.1038/nm.4394.

Linda Yang ¹, Chih-Chuan Chang ¹, Zhe Sun ¹, Dennis Madsen ², Haisun Zhu ¹, Søren B Padkjær ², Xiaoai Wu ¹, Tao Huang ¹, Karin Hultman ², Sarah J Paulsen ², Jishu Wang ¹, Anne Bugge ², Jane Boesen Frantzen ², Per Nørgaard ², Jacob Fuglsbjerg Jeppesen ², Zhiru Yang ¹, Anna Secher ², Haibin Chen ¹, Xun Li ¹, Linu Mary John ², Bing Shan ¹, Zhenhua He ¹, Xiang Gao ¹, Jing Su ¹, Kristian T Hansen ², Wei Yang ¹, Sebastian Beck Jørgensen ²

Affiliations

1 Novo Nordisk Research Centre China, Novo Nordisk A/S, Beijing, China.
2 Global Research, Novo Nordisk A/S, Maaloev, Denmark.

PMID: 28846099 DOI: 10.1038/nm.4394

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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