Nothing Special   »   [go: up one dir, main page]
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand

Nature Medicine volume 23, pages 1158–1166 (2017)Cite this article

Subjects

Abstract

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Identification of interaction between GDF15 and GFRAL.
Figure 2: Identification of RET as the GFRAL coreceptor.
Figure 3: Intracellular signaling of GDF15.
Figure 4: GFRAL and RET CNS distribution.
Figure 5: Lack of GFRAL prevented the anti-obesity actions of GDF15.
Figure 6: Mechanism driving GDF15-induced weight loss.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Macia, L. et al. Macrophage inhibitory cytokine 1 (MIC-1/GDF15) decreases food intake, body weight and improves glucose tolerance in mice on normal & obesogenic diets. PLoS One 7, e34868 (2012).

    Article  CAS  Google Scholar 

  3. Chrysovergis, K. et al. NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism. Int. J. Obes. 38, 1555–1564 (2014).

    Article  CAS  Google Scholar 

  4. Tsai, V.W. et al. Serum levels of human MIC-1/GDF15 vary in a diurnal pattern, do not display a profile suggestive of a satiety factor and are related to BMI. PLoS One 10, e0133362 (2015).

    Article  Google Scholar 

  5. Tsai, V.W. 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).

    Article  Google Scholar 

  6. Böttner, M. et al. Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1). Gene 237, 105–111 (1999).

    Article  Google Scholar 

  7. Bootcov, M.R. et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc. Natl. Acad. Sci. USA 94, 11514–11519 (1997).

    Article  CAS  Google Scholar 

  8. Valdimarsdottir, G. & Mummery, C. Functions of the TGFbeta superfamily in human embryonic stem cells. APMIS 113, 773–789 (2005).

    Article  CAS  Google Scholar 

  9. Herpin, A., Lelong, C. & Favrel, P. Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans. Dev. Comp. Immunol. 28, 461–485 (2004).

    Article  CAS  Google Scholar 

  10. Chen, W. & Ten Dijke, P. Immunoregulation by members of the TGFβ superfamily. Nat. Rev. Immunol. 16, 723–740 (2016).

    Article  Google Scholar 

  11. Airaksinen, M.S., Holm, L. & Hätinen, T. Evolution of the GDNF family ligands and receptors. Brain Behav. Evol. 68, 181–190 (2006).

    Article  Google Scholar 

  12. Artz, A., Butz, S. & Vestweber, D. GDF-15 inhibits integrin activation and mouse neutrophil recruitment through the ALK-5/TGF-βRII heterodimer. Blood 128, 529–541 (2016).

    Article  CAS  Google Scholar 

  13. Liu, D.D., Lu, J.M., Zhao, Q.R., Hu, C. & Mei, Y.A. Growth differentiation factor-15 promotes glutamate release in medial prefrontal cortex of mice through upregulation of T-type calcium channels. Sci. Rep. 6, 28653 (2016).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Fairlie, W.D. et al. Epitope mapping of the transforming growth factor-beta superfamily protein, macrophage inhibitory cytokine-1 (MIC-1): identification of at least five distinct epitope specificities. Biochemistry 40, 65–73 (2001).

    Article  CAS  Google Scholar 

  16. Baloh, R.H., Enomoto, H., Johnson, E.M. Jr. & Milbrandt, J. The GDNF family ligands and receptors—implications for neural development. Curr. Opin. Neurobiol. 10, 103–110 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Airaksinen, M.S., Titievsky, A. & Saarma, M. GDNF family neurotrophic factor signaling: four masters, one servant? Mol. Cell. Neurosci. 13, 313–325 (1999).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  20. Scott, R.P. & Ibanez, C.F. Determinants of ligand binding specificity in the glial cell line-derived neurotrophic factor family receptor alpha S. J. Biol. Chem. 276, 1450–1458 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Mazagova, M. et al. Genetic deletion of growth differentiation factor 15 augments renal damage in both type 1 and type 2 models of diabetes. Am. J. Physiol. Renal Physiol. 305, F1249–F1264 (2013).

    Article  CAS  Google Scholar 

  23. Heger, J. et al. Growth differentiation factor 15 acts anti-apoptotic and pro-hypertrophic in adult cardiomyocytes. J. Cell. Physiol. 224, 120–126 (2010).

    CAS  PubMed  Google Scholar 

  24. Kempf, T. et al. The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ. Res. 98, 351–360 (2006).

    Article  CAS  Google Scholar 

  25. Park, H., Kim, C.H., Jeong, J.H., Park, M. & Kim, K.S. GDF15 contributes to radiation-induced senescence through the ROS-mediated p16 pathway in human endothelial cells. Oncotarget 7, 9634–9644 (2016).

    PubMed  PubMed Central  Google Scholar 

  26. Wong, A. et al. Phosphotyrosine 1062 is critical for the in vivo activity of the Ret9 receptor tyrosine kinase isoform. Mol. Cell. Biol. 25, 9661–9673 (2005).

    Article  CAS  Google Scholar 

  27. Strelau, J. et al. Progressive postnatal motoneuron loss in mice lacking GDF-15. J. Neurosci. 29, 13640–13648 (2009).

    Article  CAS  Google Scholar 

  28. Tsai, V.W. et al. TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator. PLoS One 8, e55174 (2013).

    Article  CAS  Google Scholar 

  29. Mwangi, S.M. et al. Glial cell line-derived neurotrophic factor protects against high-fat diet-induced obesity. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G515–G525 (2014).

    Article  CAS  Google Scholar 

  30. Lebrun, B., Bariohay, B., Moyse, E. & Jean, A. Brain-derived neurotrophic factor (BDNF) and food intake regulation: a minireview. Auton. Neurosci. 126-127, 30–38 (2006).

    Article  CAS  Google Scholar 

  31. Quartu, M. 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).

    Article  CAS  Google Scholar 

  32. Yang, C., Hutto, D. & Sah, D.W. Distribution of GDNF family receptor alpha3 and RET in rat and human non-neural tissues. J. Mol. Histol. 37, 69–77 (2006).

    Article  CAS  Google Scholar 

  33. Norgren, R. & Smith, G.P. A method for selective section of vagal afferent or efferent axons in the rat. Am. J. Physiol. 267, R1136–R1141 (1994).

    Article  CAS  Google Scholar 

  34. Moran, T.H., Baldessarini, A.R., Salorio, C.F., Lowery, T. & Schwartz, G.J. Vagal afferent and efferent contributions to the inhibition of food intake by cholecystokinin. Am. J. Physiol. 272, R1245–R1251 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Novo Nordisk Research Centre China, Novo Nordisk A/S, Beijing, China

    Linda Yang, Chih-Chuan Chang, Zhe Sun, Haisun Zhu, Xiaoai Wu, Tao Huang, Jishu Wang, Zhiru Yang, Haibin Chen, Xun Li, Bing Shan, Zhenhua He, Xiang Gao, Jing Su & Wei Yang

  2. Global Research, Novo Nordisk A/S, Maaloev, Denmark

    Dennis Madsen, Søren B Padkjær, Karin Hultman, Sarah J Paulsen, Anne Bugge, Jane Boesen Frantzen, Per Nørgaard, Jacob Fuglsbjerg Jeppesen, Anna Secher, Linu Mary John, Kristian T Hansen & Sebastian Beck Jørgensen

Authors
  1. Linda Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chih-Chuan Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhe Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dennis Madsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haisun Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Søren B Padkjær
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaoai Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Karin Hultman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sarah J Paulsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jishu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Anne Bugge
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jane Boesen Frantzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Per Nørgaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jacob Fuglsbjerg Jeppesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Zhiru Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Anna Secher
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Haibin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Xun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Linu Mary John
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Bing Shan
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Zhenhua He
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Xiang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Jing Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Kristian T Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Wei Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Sebastian Beck Jørgensen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.Y.: library screening, flow cytometry and SPR binding assay, data collection and analysis, manuscript preparation; S.B.J.: project leadership, in vivo experiments, data collection and analysis, manuscript preparation); C.-C.C.: study supervision, manuscript preparation; Z.S.: library cell transfection; H.Z.: molecular cloning and protein expression; X.W.: Protein purification; T.H.: SPR kinetics assay; J.W.: library DNA preparation; Z.Y.: study supervision; H.C.: library DNA preparation; X.L.: bioinformatics analysis; B.S.: library-protein purification; Z.H.: cell-signaling assay, data analysis, manuscript preparation; X.G.: MIC-1 protein generation; J.S.: study supervision; W.Y.: study supervision; K.T.H.: project leadership, manuscript preparation; A.B.: qPCR tissue analysis, data collection and data analysis; J.B.F. and P.N.: expression and purification of biotinylated MIC-1 protein); K.H. and A.S.: ISH/IHC, manuscript preparation, data collection and analysis; L.M.J. and J.F.J.: indirect calorimetry, data collection and analysis; S.J.P.: laser-capture microscopy and NanoString-analysis data collection and analysis; S.B.P.: NN6K library sequence collection and analysis; D.M.: established data management and information-flow system for NN6k production and screening campaign.

Corresponding author

Correspondence to Sebastian Beck Jørgensen.

Ethics declarations

Competing interests

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.

Supplementary information

Supplementary Figures and Tables

Supplementary Figures 1–7 and Supplementary Tables 1–2. (PDF 1086 kb)

Life Sciences Reporting Summary (PDF 206 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4394

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research