Cross-species studies in humans, dogs, and mice support MC3R having a conserved role across mammals in controlling growth and pubertal timing, while complete loss of MC3R does not result in a penetrant human obesity syndrome.
Key Findings
Results
Nine individuals homozygous for functionally null MC3R variants were identified across three large consanguineously enriched cohorts totalling approximately 300,000 people.
Three large consanguineously enriched human cohorts were studied.
Total cohort size was approximately 300,000 people.
Nine homozygous carriers of functionally null MC3R variants were identified.
Six of the nine homozygotes had a BMI less than 30 kg/m2.
Results
The BMI of homozygous MC3R variant carriers was not significantly different from that of age, sex, and demographically matched controls.
Six of the nine homozygotes had a BMI below 30 kg/m2.
Comparison was made against age, sex, and demographically matched controls.
The finding indicates that complete loss of MC3R does not result in a penetrant human obesity syndrome.
This was observed across three distinct large human cohorts.
Results
A canine MC3R missense variant (p.M320I) common in Labrador Retrievers was found to significantly impair receptor signalling.
The variant identified was p.M320I in the canine MC3R gene.
This variant is common in Labrador Retrievers.
The variant was shown to significantly impair receptor signalling in functional assays.
Dogs homozygous for p.M320I were lighter and showed delayed pubertal development.
Homozygous dogs were not significantly more obese than wild-type or heterozygous dogs.
Results
Lack of Mc3r delayed pubertal development in both male and female mice.
Studies were conducted in Mc3r knockout mice.
Delayed pubertal development was observed in both sexes.
This finding is consistent with the canine and human data implicating MC3R in pubertal timing.
The mouse data support a conserved mammalian role for MC3R in controlling pubertal development.
Results
Male carriers of rare loss-of-function MC3R variants had delayed peak weight velocity and genital development but showed no evidence for excess body fat compared to non-carriers.
Growth and pubertal trajectories of individuals carrying rare loss-of-function MC3R variants were studied.
Male carriers specifically showed delayed peak weight velocity.
Male carriers also showed delayed genital development.
No evidence for excess body fat was found compared to non-carriers.
This was assessed using pubertal trajectory analysis in a human cohort.
Background
MC4R is primarily concerned with the control of appetite and energy expenditure, while MC3R is more closely related to the control of linear growth and the timing of puberty.
Both MC3R and MC4R receive neuropeptide signals from hypothalamic POMC- and AGRP-expressing neurons.
These neurons sense nutritional state directly and indirectly.
The role of MC3R in the long-term control of energy balance and body composition is described as less clear, particularly in humans.
This distinction motivated the cross-species investigation.
Conclusions
MC3R has a conserved role across mammals in controlling growth and pubertal timing, and MC3R deficiency may influence linear growth and body composition without causing penetrant obesity.
Evidence was derived from three species: humans, domestic dogs, and mice.
The cross-species convergence supports conservation of MC3R function in pubertal timing.
While MC3R deficiency may influence linear growth and body composition, complete loss does not cause a penetrant human obesity syndrome.
The authors state results 'support MC3R having a conserved role across mammals in controlling growth and pubertal timing.'
Duckett K, McClellan A, Corbin L, Cimino I, Elhakeem A, Goncalves Soares A, et al.. (2026). Cross-species studies implicate the melanocortin 3 receptor more strongly in the control of pubertal development than energy balance.. Molecular metabolism. https://doi.org/10.1016/j.molmet.2025.102301