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Nat Med. 2018 May;24(5):551-555. doi: 10.1038/s41591-018-0015-9. Epub 2018 May 7.

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

Author information

1
Sorbonne Université, INSERM, NutriOmics team, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.
2
Institute for Experimental Pediatric Endocrinology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
3
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
4
Rhythm Pharmaceuticals, Boston, MA, USA.
5
Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
6
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
7
Department of Dermatology and Allergy, Clinical Research Center for Hair and Skin Science, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
8
Center for Chronic Sick Children, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
9
Department of Pediatric Cardiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
10
Department of Endocrinology, Diabetes, and Nutrition and Charité Center for Cardiovascular Research, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
11
Department of Pediatric Endocrinology and Diabetes, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
12
Institute for Experimental Pediatric Endocrinology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany. peter.kuehnen@charite.de.

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.

PMID:
29736023
DOI:
10.1038/s41591-018-0015-9

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