Sex-differential associations of MC3R p.F45S with human metabolic profile

Obesity and related metabolic disorders represent major global health challenges, highlighting the importance of understanding the central regulation of energy homeostasis. The melanocortin system is a conserved circuitry governing food intake and other neuroendocrine processes. Within this system, the melanocortin-3 receptor (MC3R) regulates energy and glucose balance, body composition, and linear growth in rodent models, with evidence of sexually dimorphic expression and function. Whether MC3R exerts similar sex-specific effects in humans remains unclear, largely due to the rarity of loss-of-function (LoF) variants. We analysed data from the UK Biobank (UKB), a population-based study comprising 500,000 individuals, to investigate the phenotypic consequences of the rare MC3R LoF variant rs143321797 (p.F45S). Using the largest UKB whole-genome sequencing dataset to date, we performed comprehensive phenotypic analyses, including the first sex-stratified assessment of this variant. Carriage of the MC3R p.F45S variant was associated with differences in adult stature and the timing of sexual maturation. Though the variant was not associated with increased risk of obesity or metabolic disease, carriers exhibited an altered adipose tissue distribution profile characterised by relatively greater subcutaneous fat deposition. Our findings independently validate the role of MC3R in human stature and sexual maturation and identify a previously unreported association with adipose tissue distribution. The absence of increased obesity or metabolic disease risk in MC3R p.F45S carriers of this study, together with a subcutaneous-biased adipose distribution, suggests that MC3R may influence metabolic health through regulation of adipose tissue distribution rather than overall adiposity.