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GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates

Abstract

Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-β family, is a secreted protein that circulates as a 25-kDa dimer. In humans, elevated GDF15 correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor α–like (GFRAL), a distant relative of receptors for a distinct class of the TGF-β superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity.

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Figure 1: GDF15 drives body-weight loss through food-intake reduction in mice and nonhuman primates.
Figure 2: GDF15 binds to GFRAL.
Figure 3: GFRAL attenuates diet-induced obesity and insulin resistance.
Figure 4: GFRAL is necessary for GDF15-mediated food intake reduction and weight loss.
Figure 5: GDF15–GFRAL interaction is necessary but not sufficient for the effects of GDF15.
Figure 6: GDF15 induces GFRAL interaction with coreceptor RET to enable downstream signaling.

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Acknowledgements

We thank the following people for technical assistance in carrying out this work: B. Geist, Y. Wang, L. Lu, M. Husovsky (all at Janssen Research and Development). We thank E. Chi, S. Fenton, V. Stojanovic-Susulic, R. Swanson, J. Leonard and M. Erion (Janssen Research and Development) for support and insightful discussions. S.C.B., T.D.C.-M., C.R.C., and V.J.S. were employees of Kelly Outsourcing & Consulting Group. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the US National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.

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J.L.F., S.N., C.H., C.-N.C., M.J.H. and X.L.-S. contributed to protein design, generation and characterization. A.A.A. contributed to data interpretation and performed homology modeling. T.Q.D. designed and executed SPR experiments. J.A.C., S.C.B., V.J.S., X.L-S., C.-N.C. designed and executed in vitro studies. S.E.M. and S.M.R. designed all animal experiments which were executed by S.E.M., T.D.C.-M., and C.R.C. S.E.M., X.L.-S., C.-N.C., J.A.C. and S.M.R. contributed to all study design, data interpretation and wrote the manuscript.

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Correspondence to Shamina M Rangwala.

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All the authors are currently employed by Janssen Research and Development, as full-time employees or as contractors via Kelly Outsourcing & Consulting Group. There are patent documents related to this work.

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Mullican, S., Lin-Schmidt, X., Chin, CN. et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med 23, 1150–1157 (2017). https://doi.org/10.1038/nm.4392

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