Cross-species studies implicate the melanocortin 3 receptor more strongly in the control of pubertal development than energy balance

作者：Katie Duckett, Alyce McClellan, Laura J. Corbin, Irène Cimino, Ahmed Elhakeem, Ana Gonçalves Soares, Alice Williamson, Eloise Cross, Zammy Fairhurst-Hunter, Slavé Petrovski, Debra Rimmington, Jesús Alegre-Díaz, Jaime Berúmen, Pablo Kuri‐Morales, Roberto Tapia‐Conyer, Jacek Mokrosiński, I. Sadaf Farooqi, Asif Rasheed, Danish Saleheen, Adam S. Butterworth, Nicholas J. Timpson, Anthony P. Coll, Eleanor Raffan, Brian Lam, Stephen O’Rahilly · 发表于：Molecular Metabolism · 年份：2025 · DOI：10.1016/j.molmet.2025.102301 · 被引用次数：4 · 研究领域：Regulation of Appetite and Obesity、Hypothalamic control of reproductive hormones、Biochemical Analysis and Sensing Techniques

. We detected a canine MC3R missense variant (p.M320I) which is common in labrador retrievers and showed that this significantly impairs receptor signalling. Dogs homozygous for p.M320I were lighter and showed delayed pubertal development but were not significantly more obese than wild-type or heterozygous dogs. We also established that the lack of Mc3r delayed pubertal development in both male and female mice. Finally, we studied growth and pubertal trajectories of individuals carrying rare loss-of-function MC3R variants and found that male carriers had delayed peak weight velocity and genital development but had no evidence for excess body fat compared to non-carriers. Our results support MC3R having a conserved role across mammals in controlling growth and pubertal timing. While MC3R deficiency may influence linear growth and body composition, complete loss of MC3R does not result in a penetrant human obesity syndrome.