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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The monoclonal MIC-1 antibody (MAB26) was a kind gift of S. Breit (St Vincent's Hospital, Sydney, Australia). J. Jelsing and N. Vrang (Gubra, Denmark) are acknowledged for their skillful conduction of in vivo study of rats using selective vagal deafferentiation, as well as data analysis. Z. Wang (NN Research Centre, China) is acknowledged for generating GFRAL and RET cotransfected cells. X. Sun, X. Yang, X. Liu, and J. Chen (NN Research Centre, China) are acknowledged for skillful conduction of in vitro studies. The authors would also like to thank K.E. Pedersen, H. Andersen, P.G. Mortensen (NN Global Research, Denmark), L. Wang, W. Wang, T. Li, W. Liu, Y. Du, J. Xu, D. Liu, and Y. Zhao (NN Research Centre, China) for their excellent technical support.
All authors are or have been working for Novo Nordisk A/S, a pharmaceutical company producing and selling medicine for the treatment of diabetes and obesity.
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Yang, L., Chang, CC., Sun, Z. et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med 23, 1158–1166 (2017). https://doi.org/10.1038/nm.4394
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