Leptin

Cell biology

Biology

Agonism

Calcineurin

Melanocortin

NFAT

Weight loss

Transplantation

Endocrinology

Receptor

Agonist

Signal transduction

Leptin receptor

Melanocortin 4 receptor

Politics

Political science

Internal medicine

Pharmacology

Medicine

Obesity

Nature Medicine

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&nbsp;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. Treatment with setmelanotide, a new-generation MC4R agonist, provides durable weight loss in hyperphagic, leptin receptor–deficient patients, suggesting a pharmacological avenue to treat patients with various MC4R pathway defects.

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