Brief Communication

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

  • Nature Medicinevolume 24pages551555 (2018)
  • doi:10.1038/s41591-018-0015-9
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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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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.

Author information

Author notes

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

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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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.

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.

Corresponding author

Correspondence to Peter Kühnen.

Supplementary information

  1. Supplementary Text and Figures

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

  2. Reporting Summary

Source data

  1. Supplementary Data

    Source Data for Figure 2