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.