A recent study has revealed that a sensor in the brain may explain why humans are growing taller and reaching puberty earlier than ever before.
The melanocortin system
The leptin-melanocortin pathway is fundamental in the regulation of energy homeostasis. During the fed state, circulating hormones (e.g., leptin and insulin) bind to POMC neurons and produce the α-melanocyte stimulating hormone (α-MSH). Consequently, this activates the MC4R receptor, which results in the suppression of appetite.
Humans and mice that lack MD4R are obese, hyperphagic and have reduced basal energy expenditure. However, they also have normal or even accelerated early growth and no retardation of pubertal development. Both of these are impaired by caloric deprivation or leptin deficiency. This suggests that either POMC-derived peptides are not responsible for signalling to those downstream processes or that a different receptor is involved.
The only other melanocortin receptor that is predominantly expressed in the brain is MC3R. Researchers have found that mice lacking this gene have normal reproductive development, fertility and no changes in food intake. However, they do develop an altered body composition. Previous genome-wide association studies (GWAS) have found common variants in the region of MCR4 that have been associated with adult height and age of first menstruation.
The role of MC3R in human physiology
In a new study, published in Nature, researchers aimed to establish the role of MC3R in human physiology by identifying mutations that result in functional impairment of the receptor and the subsequent human phenotypes. The team specifically used whole-exome sequence data from the UK Biobank.
The team found that individuals with loss-of-function mutations in the MC3R gene had a later onset of puberty. They also found that these individuals had reduced linear growth, lean mass and circulating levels of IGF1 (manages the effects of growth hormone). One individual was actually homozygous for this mutation, which is extremely rare. This person was of short stature and started puberty after the age of 20.
Additionally, the researchers found that mice lacking Mc3r also had delayed sexual maturation and showed striking insensitivity to the reproductive impact of a period of fasting.
Overall, these findings suggest signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and timing of sexual maturation. This provides a potential mechanistic basis for the trend towards taller human height and earlier onset of puberty that has been observed with higher levels of caloric availability.
This discovery could help in the development of drugs for children with serious delays in growth and puberty.
Prof Sir Stephen O’Rahilly, study author, said:
“Future research should investigate if drugs that selectively activate the MC3R might help redirect calories into muscle and other lean tissues, with the prospect of improving the physical functionality of such patients.”
Image credit: canva