Melanocortin-4 Receptor Regulation of Endocrine Axes and Clinical Effects of Setmelanotide.
Abstract
Background
Bardet-Biedl syndrome (BBS) is a rare ciliopathy characterized 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.
Methods
In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally. Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.
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.
Interpretation
Setmelanotide exerts pleiotropic effects beyond weight reduction, modulating multiple endocrine axes in BBS. The observed changes highlight MC4R signaling pathway as a key integrator of metabolic and endocrine function and suggest partially weight-independent therapeutic effects.
Funding
German Federal Ministry of Research and Education and Rhythm Pharmaceuticals.