MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency

Abstract

Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45–61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.

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Fig. 1: Body weight course and hunger-score during setmelanotide treatment.
Fig. 2: Determination of PLC activation after challenge with setmelanotide, α-MSH and LY2112688.

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Acknowledgements

We thank D. Schnabel for his support and A. Stielow, S. Zvorc, S. Jyrch, and C. Cetindag (Charité Universitätsmedizin Berlin, Germany) and H. Guermoudi, V. Lemoine and F. Marchelli (Pitié-Sapêtrière hospital, Paris, France) for excellent study assistance. This work was supported by grants from the German Research Foundation (DFG) (KU 2673/2-1; SPP1629: BI839/5-2, KR1701/5-1; KFO218 and HI 865/2-1), Bundesministerium für Bildung und Forschung (BMBF) (NGFN- Plus, 01GS0820), the Helmholtz Association (ICEMED) (WB19) and the Institute of Cardiometabolism and Nutrition (K.C.) as well as Assistance Publique Hôpitaux de Paris (clinical research contracts to K.C. and C.P.) and Institut Benjamin Delessert. P.K. was supported by the Charité /Berlin Institute of Health (BIH) Clinical Scientist Program. H.K. and K.M. were supported by the Berlin Institute of Health (BIH). P.S. was supported by the DFG (SFB740-B6, SFB1078-B6), and G.K. and P.S. were supported by the DFG Cluster of Excellence ‘Unifying Concepts in Catalysis’ (Research Field E). I.S.F. was supported by the Wellcome Trust.

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P.K., H.K., K.G and F.F. designed the clinical study and developed the protocol; P.K., B.W. and L.P. performed the clinical investigation of the patients; P.K. supervised and managed data generation and analysis; K.C. and C.P. recruited subject 1 and 3 and performed routine follow-up; I.S.F. recruited subject 2; U.B-P. and I.J. performed regular dermatological examination; K.W. was involved as a cardiologist; K.M. and J.S. contributed to the clinical investigation and metabolic phenotyping (including data analysis) of the individuals; S.W. supported clinical investigation of the patients; H.B., A.M. and L.V.d.P. performed in vitro experiments; P.K., H.B., A.M., J.M, I.S.F. and L.V.d.P. critically discussed the results of in vitro experiments; A.G., O.B. and S.S. contributed to the discussion of the data; G.K., N.H. and P.S. performed the MC4 receptor modeling and docking studies, analyzed the structural data and described related parts; P.K., L.V.d.P., H.B., H.K., K.G., I.S.F., K.C., F.F., G.K., N.H. and P.S. contributed to the analysis and interpretation of the data and reviewed all drafts of the manuscript.

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Correspondence to Peter Kühnen.

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Competing interests

L.V.d.P., F.F. and K.G. are employees and stock holders of Rhythm Pharmaceuticals. S. Sharma is a consultant for Rhythm Pharmaceuticals.

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Supplementary Note, Supplementary Figures 1–10 and Supplementary Tables 1–5

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Source Data for Figure 2

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Clément, K., Biebermann, H., Farooqi, I.S. et al. MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med 24, 551–555 (2018). https://doi.org/10.1038/s41591-018-0015-9

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