Melanocortin-4 Receptor Regulation of Endocrine Axes and Clinical Effects of Setmelanotide

Background: Bardet–Biedl syndrome (BBS) is a rare ciliopathy characterised by early-onset obesity and multisystem endocrine dysfunction. The melanocortin-4 receptor (MC4R) agonist setmelanotide is approved for hyperphagia-related obesity in BBS, but its endocrine effects remain incompletely understood.<br><br>Methods: In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide were followed longitudinally. Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.<br><br>Findings: After 6 months, significant reductions in BMI and HbA1c were observed. Treatment was associated with increases in gonadotropins and testosterone and estradiol age-dependently. IGF-1 levels increased independently of weight change, while TSH decreased without corresponding changes in peripheral thyroid hormones. These effects were established within the first 6 months and remained stable thereafter.<br><br>Interpretation: Setmelanotide exerts pleiotropic effects beyond weight reduction, modulating multiple endocrine axes in BBS. The observed changes highlight MC4R signalling pathway as a key integrator of metabolic and endocrine function and suggest partially weight-independent therapeutic effects.​