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The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL

Nature Medicine volume 23, pages 1215–1219 (2017)Cite this article

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Abstract

Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant member of the transforming growth factor-β (TGF-β) superfamily and has been implicated in various biological functions, including cancer cachexia, renal and heart failure, atherosclerosis and metabolism1. A connection between GDF15 and body-weight regulation was initially suggested on the basis of an observation that increasing GDF15 levels in serum correlated with weight loss in individuals with advanced prostate cancer2. In animal models, overexpression of GDF15 leads to a lean phenotype, hypophagia and other improvements in metabolic parameters3, suggesting that recombinant GDF15 protein could potentially be used in the treatment of obesity and type 2 diabetes. However, the signaling and mechanism of action of GDF15 are poorly understood owing to the absence of a clearly identified cognate receptor. Here we report that GDNF-family receptor α-like (GFRAL), an orphan member of the GFR-α family, is a high-affinity receptor for GDF15. GFRAL binds to GDF15 in vitro and is required for the metabolic actions of GDF15 with respect to body weight and food intake in vivo in mice. Gfral−/− mice were refractory to the effects of recombinant human GDF15 on body-weight, food-intake and glucose parameters. Blocking the interaction between GDF15 and GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in rats. Gfral mRNA is highly expressed in the area postrema of mouse, rat and monkey, in accordance with previous reports implicating this region of the brain in the metabolic actions of GDF15 (refs. 4,5,6). Together, our data demonstrate that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15.

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Figure 1: GFRAL interacts with GDF15.
Figure 2: GDF15 does not suppress body weight and food intake in Gfral−/− mice.
Figure 3: GFRAL antibody blocks GDF15-induced body-weight and food-intake suppression in Sprague–Dawley rats.
Figure 4: Gfral expression in brain tissue from different species and continuous food-intake monitoring.

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Acknowledgements

We thank J. Shou, X. Wu and D. Accili for helpful suggestions on the manuscript.

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  1. Paul J Emmerson, Feng Wang, Yong Du, Qian Liu and Richard T Pickard: These authors contributed equally to this work.

Authors and Affiliations

  1. Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly & Company, Indianapolis, Indiana, USA

    Paul J Emmerson, Richard T Pickard, Malgorzata D Gonciarz, Tamer Coskun, Matthew J Hamang, Dana K Sindelar, Kimberly K Ballman, Lisa A Foltz, Avinash Muppidi, Jorge Alsina-Fernandez, Gavin C Barnard, Jason X Tang, Robert Siegel, John H Sloan, Pamela J Mitchell & Ruth E Gimeno

  2. Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China

    Feng Wang, Yong Du, Qian Liu, Xilin Liu, Xudong Mao, Bei B Zhang, Bei Shan & Xinle Wu

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Contributions

P.J.E., M.D.G., T.C., R.S., R.E.G., B.B.Z., B.S. and X.W. designed and supervised the research. F.W., Y.D., Q.L., R.T.P., T.C., M.J.H., K.K.B., D.K.S., L.A.F., A.M., J.A.-F., G.C.B., J.X.T., X.L., X.M., P.J.M. and J.H.S. performed research. P.J.E., M.D.G., T.C., R.S. and X.W. analyzed data. P.J.E. and X.W. wrote the manuscript.

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Correspondence to Xinle Wu.

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All authors declare competing financial interests as employees of Eli Lilly and Company.

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Emmerson, P., Wang, F., Du, Y. et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat Med 23, 1215–1219 (2017). https://doi.org/10.1038/nm.4393

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