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

Nat Med. 2018 May;24(5):551-555. doi: 10.1038/s41591-018-0015-9. Epub 2018 May 7.


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.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Enzyme Activation / drug effects
  • HEK293 Cells
  • Humans
  • Male
  • Peptides / pharmacology
  • Receptor, Melanocortin, Type 4 / agonists*
  • Receptors, Leptin / deficiency*
  • Receptors, Leptin / genetics
  • Type C Phospholipases / metabolism
  • Weight Loss* / drug effects
  • Young Adult
  • alpha-MSH / analogs & derivatives
  • alpha-MSH / pharmacology


  • LY2112688
  • Peptides
  • Receptor, Melanocortin, Type 4
  • Receptors, Leptin
  • setmelanotide
  • alpha-MSH
  • Type C Phospholipases