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

Nature. 2021 Nov;599(7885):436-441. doi: 10.1038/s41586-021-04088-9. Epub 2021 Nov 3.


The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. 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 that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the 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, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Aged, 80 and over
  • Animals
  • Child
  • Child Development / physiology*
  • Estrous Cycle / genetics
  • Estrous Cycle / physiology
  • Female
  • Homozygote
  • Humans
  • Hypothalamus / cytology
  • Hypothalamus / physiology
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Melanocortins / metabolism
  • Menarche / genetics
  • Menarche / physiology
  • Mice
  • Nutritional Status / physiology*
  • Phenotype
  • Puberty / genetics
  • Puberty / physiology*
  • Receptor, Melanocortin, Type 3 / deficiency
  • Receptor, Melanocortin, Type 3 / genetics
  • Receptor, Melanocortin, Type 3 / metabolism*
  • Sexual Maturation / genetics
  • Sexual Maturation / physiology*
  • Time Factors
  • Weight Gain


  • IGF1 protein, human
  • MC3R protein, human
  • Mc3r protein, mouse
  • Melanocortins
  • Receptor, Melanocortin, Type 3
  • Insulin-Like Growth Factor I