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

Nature Medicine volume 24, pages 551–555 (2018)Cite this article

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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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Fig. 1: Body weight course and hunger-score during setmelanotide treatment.
Fig. 2: Determination of PLC activation after challenge with setmelanotide, α-MSH and LY2112688.

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Acknowledgements

We thank D. Schnabel for his support and A. Stielow, S. Zvorc, S. Jyrch, and C. Cetindag (Charité Universitätsmedizin Berlin, Germany) and H. Guermoudi, V. Lemoine and F. Marchelli (Pitié-Sapêtrière hospital, Paris, France) for excellent study assistance. This work was supported by grants from the German Research Foundation (DFG) (KU 2673/2-1; SPP1629: BI839/5-2, KR1701/5-1; KFO218 and HI 865/2-1), Bundesministerium für Bildung und Forschung (BMBF) (NGFN- Plus, 01GS0820), the Helmholtz Association (ICEMED) (WB19) and the Institute of Cardiometabolism and Nutrition (K.C.) as well as Assistance Publique Hôpitaux de Paris (clinical research contracts to K.C. and C.P.) and Institut Benjamin Delessert. P.K. was supported by the Charité /Berlin Institute of Health (BIH) Clinical Scientist Program. H.K. and K.M. were supported by the Berlin Institute of Health (BIH). P.S. was supported by the DFG (SFB740-B6, SFB1078-B6), and G.K. and P.S. were supported by the DFG Cluster of Excellence ‘Unifying Concepts in Catalysis’ (Research Field E). I.S.F. was supported by the Wellcome Trust.

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Author notes

  1. These authors contributed equally: Karine Clément, Heike Biebermann, I. Sadaf Farooqi, Lex Van der Ploeg.

Authors and Affiliations

  1. Sorbonne Université, INSERM, NutriOmics team, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France

    Karine Clément & Christine Poitou

  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

    Heike Biebermann, Barbara Wolters, Lia Puder, Anne Müller, Oliver Blankenstein, Heiko Krude & Peter Kühnen

  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

    I. Sadaf Farooqi & Jacek Mokrosinski

  4. Rhythm Pharmaceuticals, Boston, MA, USA

    Lex Van der Ploeg, Fred Fiedorek, Keith Gottesdiener & Shubh Sharma

  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

    Gunnar Kleinau, Nicolas Heyder & Patrick Scheerer

  6. DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany

    Patrick Scheerer, Knut Mai & Joachim Spranger

  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

    Ulrike Blume-Peytavi & Irina Jahnke

  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

    Susanna Wiegand

  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

    Katja Weiß

  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

    Knut Mai & Joachim Spranger

  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

    Annette Grüters

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  1. Karine Clément
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Contributions

P.K., H.K., K.G and F.F. designed the clinical study and developed the protocol; P.K., B.W. and L.P. performed the clinical investigation of the patients; P.K. supervised and managed data generation and analysis; K.C. and C.P. recruited subject 1 and 3 and performed routine follow-up; I.S.F. recruited subject 2; U.B-P. and I.J. performed regular dermatological examination; K.W. was involved as a cardiologist; K.M. and J.S. contributed to the clinical investigation and metabolic phenotyping (including data analysis) of the individuals; S.W. supported clinical investigation of the patients; H.B., A.M. and L.V.d.P. performed in vitro experiments; P.K., H.B., A.M., J.M, I.S.F. and L.V.d.P. critically discussed the results of in vitro experiments; A.G., O.B. and S.S. contributed to the discussion of the data; G.K., N.H. and P.S. performed the MC4 receptor modeling and docking studies, analyzed the structural data and described related parts; P.K., L.V.d.P., H.B., H.K., K.G., I.S.F., K.C., F.F., G.K., N.H. and P.S. contributed to the analysis and interpretation of the data and reviewed all drafts of the manuscript.

Corresponding author

Correspondence to Peter Kühnen.

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Competing interests

L.V.d.P., F.F. and K.G. are employees and stock holders of Rhythm Pharmaceuticals. S. Sharma is a consultant for Rhythm Pharmaceuticals.

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Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–10 and Supplementary Tables 1–5

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Supplementary Data

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Clément, K., Biebermann, H., Farooqi, I.S. et al. MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med 24, 551–555 (2018). https://doi.org/10.1038/s41591-018-0015-9

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