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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


Primary accessions

Referenced accessions


  1. 1.

    et al. Gut-brain cross-talk in metabolic control. Cell 168, 758–774 (2017)

  2. 2.

    & Central nervous system control of metabolism. Nature 491, 357–363 (2012)

  3. 3.

    et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166, 1512–1525.e1512 (2016)

  4. 4.

    , & Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137, 1225–1234 (2009)

  5. 5.

    , , & Genetic identification of a neural circuit that suppresses appetite. Nature 503, 111–114 (2013)

  6. 6.

    , & Deciphering a neuronal circuit that mediates appetite. Nature 483, 594–597 (2012)

  7. 7.

    , & Neurobiology of food intake in health and disease. Nat. Rev. Neurosci. 15, 367–378 (2014)

  8. 8.

    , , , & Anorexia-cachexia and obesity treatment may be two sides of the same coin: role of the TGF-b superfamily cytokine MIC-1/GDF15. Int. J. Obes. 40, 193–197 (2016)

  9. 9.

    et al. Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol. Cell. Biol. 20, 3742–3751 (2000)

  10. 10.

    et al. The TGF-β superfamily cytokine, MIC-1/GDF15: a pleotrophic cytokine with roles in inflammation, cancer and metabolism. Growth Factors 29, 187–195 (2011)

  11. 11.

    et al. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat. Med. 13, 1333–1340 (2007)

  12. 12.

    et al. Identification, expression and functional characterization of the GRAL gene. J. Neurochem. 95, 361–376 (2005)

  13. 13.

    & The GDNF family: signalling, biological functions and therapeutic value. Nat. Rev. Neurosci. 3, 383–394 (2002)

  14. 14.

    et al. Characterization of a multicomponent receptor for GDNF. Nature 382, 80–83 (1996)

  15. 15.

    et al. GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell 85, 1113–1124 (1996)

  16. 16.

    , , & A mutation at tyrosine 1062 in MEN2A-Ret and MEN2B-Ret impairs their transforming activity and association with shc adaptor proteins. J. Biol. Chem. 271, 17644–17649 (1996)

  17. 17.

    et al. The structure of the glial cell line-derived neurotrophic factor-coreceptor complex: insights into RET signaling and heparin binding. J. Biol. Chem. 283, 35164–35172 (2008)

  18. 18.

    , , & Structure of artemin complexed with its receptor GFRalpha3: convergent recognition of glial cell line-derived neurotrophic factors. Structure 14, 1083–1092 (2006)

  19. 19.

    et al. The structure of GFRalpha1 domain 3 reveals new insights into GDNF binding and RET activation. EMBO J. 23, 1452–1462 (2004)

  20. 20.

    et al. The anorectic actions of the TGFβ cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract. PLoS One 9, e100370 (2014)

  21. 21.

    , & Area postrema lesions produce feeding deficits in the rat: effects of preoperative dieting and 2-deoxy-D-glucose. Physiol. Behav. 29, 875–884 (1982)

  22. 22.

    , & Area postrema/nucleus of the solitary tract ablations: analysis of the effects of hypophagia. Physiol. Behav. 32, 429–435 (1984)

  23. 23.

    et al. Spatial and temporal expression of the ret proto-oncogene product in embryonic, infant and adult rat tissues. Oncogene 10, 191–198 (1995)

  24. 24.

    et al. Tissue distribution of Ret, GFRalpha-1, GFRalpha-2 and GFRalpha-3 receptors in the human brainstem at fetal, neonatal and adult age. Brain Res. 1173, 36–52 (2007)

  25. 25.

    , , & Parabrachial CGRP neurons control meal termination. Cell Metab. 23, 811–820 (2016)

  26. 26.

    et al. Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus. Nat. Neurosci. 20, 934–942 (2017)

  27. 27.

    et al. GLP-1 receptor stimulation of the lateral parabrachial nucleus reduces food intake: neuroanatomical, electrophysiological, and behavioral evidence. Endocrinology 155, 4356–4367 (2014)

  28. 28.

    , , , & Cisplatin induces neuronal activation and increases central AMPA and NMDA receptor subunit gene expression in mice. Physiol. Behav. 136, 79–85 (2014)

  29. 29.

    et al. Excitatory hindbrain-forebrain communication is required for cisplatin-induced anorexia and weight loss. J. Neurosci. 37, 362–370 (2017)

  30. 30.

    , & Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site. J. Biol. Chem. 276, 35808–35817 (2001)

  31. 31.

    The theoretical bases of indirect calorimetry: a review. Metabolism 37, 287–301 (1988)

  32. 32.

    , & The effects on weight loss and gene expression in adipose and hepatic tissues of very-low carbohydrate and low-fat isoenergetic diets in diet-induced obese mice. Nutr. Metab. (Lond.) 13, 78 (2016)

  33. 33.

    , , & Structure determination of an FMN reductase from Pseudomonas aeruginosa PA01 using sulfur anomalous signal. Acta Crystallogr. D 62, 383–391 (2006)

  34. 34.

    , , , & Can anomalous signal of sulfur become a tool for solving protein crystal structures? J. Mol. Biol. 289, 83–92 (1999)

  35. 35.

    & [20] Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997)

  36. 36.

    Experimental phasing with SHELXC/D/E: combining chain tracing with density modification. Acta Crystallogr. D 66, 479–485 (2010)

  37. 37.

    et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007)

  38. 38.

    The Buccaneer software for automated model building. 1. Tracing protein chains. Acta Crystallogr. D 62, 1002–1011 (2006)

  39. 39.

    , , & Features and development of Coot. Acta Crystallogr. D 66, 486–501 (2010)

  40. 40.

    et al. REFMAC5 dictionary: organization of prior chemical knowledge and guidelines for its use. Acta Crystallogr. D 60, 2184–2195 (2004)

Download references


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.


  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


  1. Search for Jer-Yuan Hsu in:

  2. Search for Suzanne Crawley in:

  3. Search for Michael Chen in:

  4. Search for Dina A. Ayupova in:

  5. Search for Darrin A. Lindhout in:

  6. Search for Jared Higbee in:

  7. Search for Alan Kutach in:

  8. Search for William Joo in:

  9. Search for Zhengyu Gao in:

  10. Search for Diana Fu in:

  11. Search for Carmen To in:

  12. Search for Kalyani Mondal in:

  13. Search for Betty Li in:

  14. Search for Avantika Kekatpure in:

  15. Search for Marilyn Wang in:

  16. Search for Teresa Laird in:

  17. Search for Geoffrey Horner in:

  18. Search for Jackie Chan in:

  19. Search for Michele McEntee in:

  20. Search for Manuel Lopez in:

  21. Search for Damodharan Lakshminarasimhan in:

  22. Search for Andre White in:

  23. Search for Sheng-Ping Wang in:

  24. Search for Jun Yao in:

  25. Search for Junming Yie in:

  26. Search for Hugo Matern in:

  27. Search for Mark Solloway in:

  28. Search for Raj Haldankar in:

  29. Search for Thomas Parsons in:

  30. Search for Jie Tang in:

  31. Search for Wenyan D. Shen in:

  32. Search for Yu Alice Chen in:

  33. Search for Hui Tian in:

  34. Search for Bernard B. Allan in:


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.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains uncropped gels for Extended Data Figure 4a,b.

  2. 2.

    Reporting Summary

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.