• An Erratum to this article was published on 08 November 2017

Abstract

Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure1,2. In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand3. Recent studies have identified brain areas outside the hypothalamus that are activated under these ‘non-homeostatic’ conditions4,5,6, but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the ‘emergency circuit’ that shapes feeding responses to stressful conditions7. GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases8,9. By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.

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Acknowledgements

We thank N. Maddox, H. Tran, J. Oeffinger and R. Suriben for cloning, sequencing and genotyping, M. Bailey for purification of recombinant protein, R. Suto for help with solving the crystal structures and S. Talukdar, D. Kaplan, R. Suriben, S. Katewa and J.-L. Chen for critical reading of the manuscript.

Author information

Author notes

    • William Joo
    • , Manuel Lopez
    •  & Yu Alice Chen

    Present addresses: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA (W.J.); BioMarin Pharmaceuticals Inc., San Rafael, California 94901, USA (M.L.); 23andMe, Inc., South San Francisco, California 94080, USA (Y.A.C.).

    • Jer-Yuan Hsu
    • , Suzanne Crawley
    •  & Michael Chen

    These authors contributed equally to this work.

Affiliations

  1. NGM Biopharmaceuticals, South San Francisco, California 94080, USA

    • Jer-Yuan Hsu
    • , Suzanne Crawley
    • , Michael Chen
    • , Dina A. Ayupova
    • , Darrin A. Lindhout
    • , Jared Higbee
    • , Alan Kutach
    • , William Joo
    • , Zhengyu Gao
    • , Diana Fu
    • , Carmen To
    • , Kalyani Mondal
    • , Betty Li
    • , Avantika Kekatpure
    • , Marilyn Wang
    • , Teresa Laird
    • , Geoffrey Horner
    • , Jackie Chan
    • , Michele McEntee
    • , Manuel Lopez
    • , Hugo Matern
    • , Mark Solloway
    • , Raj Haldankar
    • , Thomas Parsons
    • , Jie Tang
    • , Wenyan D. Shen
    • , Yu Alice Chen
    • , Hui Tian
    •  & Bernard B. Allan
  2. XTAL Biostructures, 12 Michigan Drive, Natick, Massachusetts 01760, USA

    • Damodharan Lakshminarasimhan
    •  & Andre White
  3. Merck Research Labs, Kenilworth, New Jersey 07033, USA

    • Sheng-Ping Wang
    • , Jun Yao
    •  & Junming Yie

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Contributions

J.-Y.H., D.A.L., J.T., W.D.S., Y.A.C., H.T. and B.B.A. directed the work. B.B.A., J.-Y.H., and D.A.L. designed experiments, analysed data and wrote the manuscript, with comments from all of the authors. S.C. and J.-Y.H. developed methods for the library screen. S.C., J.-Y.H., D.A.A., B.L. and J.C. developed and performed cell-based assays. W.J., M.L., M.M. and M.S. performed IHC and IF experiments in brain sections. M.C. designed, managed and performed mouse experiments along with Z.G., D.F. and C.T. GLP1R knockout experiments were done by S.-P.W., J.Ya. and J.Yi. Crystal structures were solved by D.L and A.W. A.Ke and H.M. created all expression constructs. M.W., T.L., G.H., J.H., and A.Ku expressed and purified all recombinant proteins under the guidance of R.H., T.P. and D.A.L. Surface plasmon resonance experiments were performed by K.M.

Competing interests

D.L. and A.W. declare no direct competing financial interests. All other authors are or were employees of NGM Biopharmaceuticals or Merck Research Labs and may hold stock or stock options in these companies. NGM Biopharmaceuticals, Inc. has filed a non-provisional patent application entitled “Compositions and Methods for Modulating Body Weight” (PCT/US2017/020753), which discloses the GFRAL–GDF15 protein complex, and methods of identifying agents that may modulate the protein complex interaction(s) and potential uses of those agents to control body weight. J.-Y.H., S.C., J.H., J.T., W.D.S., Y.A.C. and H.T. are listed as inventors.

Corresponding authors

Correspondence to Jer-Yuan Hsu or Bernard B. Allan.

Reviewer Information Nature thanks R. Palmiter, M. Saarma and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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