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

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.

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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.

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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.

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Authors and Affiliations

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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.

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Correspondence to Sebastian Beck Jørgensen.

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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.

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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

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