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

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MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency.
Nature Medicine ( IF 82.9 ) Pub Date : 2018-May-01 , DOI: 10.1038/s41591-018-0015-9
Karine Clément ₁ , Heike Biebermann ₂ , I Sadaf Farooqi ₃ , Lex Van der Ploeg ₄ , Barbara Wolters ₂ , Christine Poitou ₁ , Lia Puder ₂ , Fred Fiedorek ₄ , Keith Gottesdiener ₄ , Gunnar Kleinau ₅ , Nicolas Heyder ₅ , Patrick Scheerer _{5,

6} , Ulrike Blume-Peytavi ₇ , Irina Jahnke ₇ , Shubh Sharma ₄ , Jacek Mokrosinski ₃ , Susanna Wiegand ₈ , Anne Müller ₂ , Katja Weiß ₉ , Knut Mai _{6,

10} , Joachim Spranger _{6,

10} , Annette Grüters ₁₁ , Oliver Blankenstein ₂ , Heiko Krude ₂ , Peter Kühnen ₂

Affiliation

Sorbonne Université, INSERM, NutriOmics team, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.
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.
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Rhythm Pharmaceuticals, Boston, MA, USA.
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.
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
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.
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.
Department of Pediatric Cardiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
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.
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.

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.

中文翻译：

MC4R激动剂可促进瘦素受体缺乏症患者的持续减肥。

melanocortin-4受体（MC4R）信号转导通路的遗传缺陷导致严重肥胖。对3名严重肥胖的LEPR缺乏者进行了MC4R激动剂setmelanotide的治疗，在45-61周的观察期内，导致了食欲亢进和体重的大量且持久的减少。与以前开发和测试的MC4R激动剂相比，赛美拉肽具有激活活化T细胞（NFAT）信号的核因子和针对所选MC4R变体恢复该信号通路的独特功能。我们的数据证明了setmelanotide在治疗各种MC4R相关途径缺乏的个体中的功效。

更新日期：2018-05-08

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