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

• DOI: 10.1038/s41591-018-0015-9
• Publication Date: 2018-05-04T09:04:04Z
• Authors: Karine Clément; Heike Biebermann; I. Sadaf Farooqi; Lex Van der Ploeg; Barbara Wolters; Christine Poitou; Lia Puder; Fred Fiedorek; Keith Gottesdiener; Gunnar Kleinau; Nicolas Heyder; Patrick Scheerer; Ulrike Blume-Peytavi; Irina Jahnke; Shubh Sharma; Jacek Mokrosinski; Susanna Wiegand; Anne Müller; Katja Weiß; Knut Mai; Joachim Spranger; Annette Grüters; Oliver Blankenstein; Heiko Krude; Peter Kühnen
• Keywords: Melanocortin 4 receptor; Agonism; NFAT; Leptin receptor

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.