Clinical Trial

. 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

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.

PubMed Disclaimer

Cited by

Immunogenetic Aspects of Sarcopenic Obesity.
Mazurkiewicz Ł, Czernikiewicz K, Grygiel-Górniak B. Mazurkiewicz Ł, et al. Genes (Basel). 2024 Feb 5;15(2):206. doi: 10.3390/genes15020206. Genes (Basel). 2024. PMID: 38397196 Free PMC article. Review.
Ascorbate-induced oxidative stress mediates TRP channel activation and cytotoxicity in human etoposide-sensitive and -resistant retinoblastoma cells.
Oronowicz J, Reinhard J, Reinach PS, Ludwiczak S, Luo H, Omar Ba Salem MH, Kraemer MM, Biebermann H, Kakkassery V, Mergler S. Oronowicz J, et al. Lab Invest. 2021 Jan;101(1):70-88. doi: 10.1038/s41374-020-00485-2. Epub 2020 Sep 18. Lab Invest. 2021. PMID: 32948812 Free PMC article.
Late onset obesity in mice with targeted deletion of potassium inward rectifier Kir7.1 from cells expressing the melanocortin-4 receptor.
Anderson EJP, Ghamari-Langroudi M, Cakir I, Litt MJ, Chen V, Reggiardo RE, Millhauser GL, Cone RD. Anderson EJP, et al. J Neuroendocrinol. 2019 Jan;31(1):e12670. doi: 10.1111/jne.12670. Epub 2019 Jan 20. J Neuroendocrinol. 2019. PMID: 30561082 Free PMC article.
A Setmelanotide-like Effect at MC4R Is Achieved by MC4R Dimer Separation.
Reininghaus N, Paisdzior S, Höpfner F, Jyrch S, Cetindag C, Scheerer P, Kühnen P, Biebermann H. Reininghaus N, et al. Biomolecules. 2022 Aug 15;12(8):1119. doi: 10.3390/biom12081119. Biomolecules. 2022. PMID: 36009013 Free PMC article.
The Narrative of a Patient with Leptin Receptor Deficiency: Personalized Medicine for a Rare Genetic Obesity Disorder.
Welling MS, Kleinendorst L, van Haelst MM, van den Akker ELT. Welling MS, et al. Obes Facts. 2023;16(5):514-518. doi: 10.1159/000531529. Epub 2023 Jul 1. Obes Facts. 2023. PMID: 37393902 Free PMC article.

See all "Cited by" articles

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

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Nature Publishing Group
Other Literature Sources
Medical
- MedlinePlus Consumer Health Information
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Authors

Affiliations

Abstract

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous

Abstract

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous