The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development 1 . The central melanocortin system acts through Melanocortin-4 Receptor (MC4R) to control appetite, food intake and energy expenditure 2 . We now present evidence that the Melanocortin-3 Receptor (MC3R) regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and IGF-1 levels. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons controlling reproduction and growth and increases during post-natal development in a manner consistent with a role in regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, while MC3R primarily regulates their disposition into growth, lean mass and the timing of sexual maturation.

Mutations in the melanocortin 4 receptor gene ( MC4R ) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development. We examined the MC4R coding sequence in 5724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterised all non-synonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss of function (LoF) mutations in MC4R was ~1/337 (0.30%), considerably higher than previous estimates. At age 18 years, mean differences in body weight, body mass index and fat mass between carriers and non-carriers of LoF mutations were 17.76kg (95% CI: 9.41, 26.10), 4.84kg/m 2 (95% CI: 2.19, 7.49) and 14.78kg (95% CI: 8.56, 20.99), respectively. MC4R LoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity.