MC3R links nutritional state to childhood growth and the timing of puberty

Abstract

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.

Significant Sparse Polygenic Risk Scores across 813 traits in UK Biobank

“…Given the medical relevance [39][40][41][42][43][44][45][46][47][48][49][50][51], we prioritized pathogenic and likely-pathogenic variants reported in ClinVar [52] as well as predicted protein-truncating and protein-altering variants (Methods). Our analysis focusing on four traits suggests that prioritizing the medically relevant alleles does not necessarily improve the predictive performance.…”

The Multifaceted Melanocortin Receptors

“…Both male and female MC 3 KO mice have impaired linear growth ( 5 ). Screening whole-exome sequence data of 200 000 individuals from the UK Biobank revealed more than 170 different variants in the human MC 3 gene ( 7 ): all are exceptionally rare. The researchers selected the 3 most common variants and performed sophisticated analyses using all 500 000 participants in the UK Biobank to demonstrate that these 3 variants were each associated with shorter stature ( 7 ).…”

“…Screening whole-exome sequence data of 200 000 individuals from the UK Biobank revealed more than 170 different variants in the human MC 3 gene ( 7 ): all are exceptionally rare. The researchers selected the 3 most common variants and performed sophisticated analyses using all 500 000 participants in the UK Biobank to demonstrate that these 3 variants were each associated with shorter stature ( 7 ). MC 3 colocalizes to growth hormone–releasing hormone neurons in the hypothalamus, and the authors suggest that MC 3 may therefore act at the level of the hypothalamus to regulate height.…”

A Brief Introduction to Darwinian Medicine

“…107 Research is constantly refining our models, and a recent 2021 article seems particularly relevant. Lam and colleagues 108 have uncovered a bifurcating model of nutrient sensing via the central melanocortin pathway, with signalling through MC4R regulating the acquisition and retention of calories, whereas signalling via MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation. Indeed, many of these ideas on evolution and ageing overlap with other paradigms such as the DOHaD.…”