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

Karine Clément^#¹, Heike Biebermann^#², I Sadaf Farooqi^#³, Lex Van der Ploeg^#⁴, Barbara Wolters², Christine Poitou¹, Lia Puder², Fred Fiedorek⁴, Keith Gottesdiener⁴, Gunnar Kleinau⁵, Nicolas Heyder⁵, Patrick Scheerer^{5

6}, Ulrike Blume-Peytavi⁷, Irina Jahnke⁷, Shubh Sharma⁴, Jacek Mokrosinski³, Susanna Wiegand⁸, Anne Müller², Katja Weiß⁹, Knut Mai^{6

10}, Joachim Spranger^{6

10}, Annette Grüters¹¹, Oliver Blankenstein², Heiko Krude², Peter Kühnen¹²

Affiliations

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.

^# Contributed equally.

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

Clinical Trial

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

Karine Clément et al. Nat Med. 2018 May.

. 2018 May;24(5):551-555.

doi: 10.1038/s41591-018-0015-9. Epub 2018 May 7.

Authors

Affiliations

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.

^# Contributed equally.

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

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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References

1. Farooqi, I. S. & O’Rahilly, S. J. Endocrinol. 223, T63–T70 (2014). - DOI
1. Krishna, R. et al. Clin. Pharmacol. Ther. 86, 659–666 (2009). - DOI
1. Farooqi, I. S. et al. N. Engl. J. Med. 341, 879–884 (1999). - DOI
1. Clément, K. et al. Nature 392, 398–401 (1998). - DOI
1. Jackson, V. M., Price, D. A. & Carpino, P. A. Expert Opin. Investig. Drugs 23, 1055–1066 (2014). - DOI

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

Affiliations

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

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Abstract

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Full Text Sources

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Medical

Miscellaneous