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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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.
Source Data for Figure 2