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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Acknowledgements

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

Author information

Author notes

    • Paul J Emmerson
    • , Feng Wang
    • , Yong Du
    • , Qian Liu
    •  & Richard T Pickard

    These authors contributed equally to this work.

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.

Competing interests

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

Corresponding author

Correspondence to Xinle Wu.

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DOI

https://doi.org/10.1038/nm.4393

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