Appearing in Nature, the study identifies the MC3R brain receptor as responsive to nutritional signals that turn that information into growth and sexual maturation.
The discovery may explain why humans have been growing taller and reaching sexual maturity earlier over the past century.
“This research may have wider implications beyond child development and reproductive health,” says Professor Sir Stephen O’Rahilly, senior study author and Director of the Medical Research Council (MRC) Metabolic Diseases Unit at the University of Cambridge.
“Many chronic diseases are associated with the loss of lean mass, including muscle, with resultant frailty. This responds poorly to simple nutritional supplements such as protein-rich drinks.
‘Improving physical function’
“The finding that the activity of the MC3R pathway influences the amount of lean mass carried by a person suggests that 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 functional of such patients.”
To test the theory, the research team began searching the UK Biobank for people with naturally occurring genetic mutations that disrupt the function of the MC3R.
They identified a few thousand people who carried various mutations in the gene for MC3R and found these people were on average shorter and went into puberty later than those with no mutation.
Further analysis identified 812 women with the same mutation in one of their two copies of the MC3R gene that partially reduced receptor function.
Despite this, these women were on average 4.7 months older at puberty than those without the mutation.
Individuals with this mutation were also shorter and had lower amounts of lean muscle tissue. However, the mutation appeared to have no effect on how much fat they carried.
Deeper analysis identified six children with MC3R mutations from the Avon Longitudinal Study of Parents and Children (ALSPAC). These children were also shorter and had lower lean mass and weight throughout childhood.
The paper notes that while those identified in these studies had a mutation in only one of the two copies of the gene, finding mutations in both copies of the gene is extremely rare.
However, they were able to find an individual from the Genes and Health study with a mutation in both gene copies resulting in a very short stature and the start of puberty after the age of 20.
“These findings have the potential to make a significant step forward in future management of disorders of growth and puberty, and improvements in the health of those suffering from frailty caused by chronic conditions,” adds Dr Rob Buckle, Chief Science Officer at the MRC, which co-funded the research.
“This study shows the value of long-term investment in both large UK population cohorts and multidisciplinary research to discover the underpinning causes of human health and disease.”
Professor John Perry, another senior study author from the MRC Epidemiology Unit at the University of Cambridge, says, “This is such an exciting time for human genetics.
“By analysing the genetic sequences of large numbers of research participants, we can now understand fundamental biological processes that have remained elusive until now.
“By combining these studies with experiments in cellular and animal models, we will continue to uncover new insights and understand the mechanisms behind human growth and metabolic disease.”
Previous studies have established that signals reach the brain to inform of the body’s nutritional state, such as insulin, produced in response to increases in blood sugar levels.
In the brain’s hypothalamus, hormones act on neurons that produce signals called melanocortins that act on a number of receptors, two of which are located in the brain.
One of these, the melanocortin 4 receptor (MC4R) has been shown to regulate appetite. In contrast, a lack of MC4R results in obesity. Previous evidence had suggested the MC4R system did not control the effect of nutrition on growth and timing of puberty.
Published online: doi.org/10.1038/s41586-021-04088-9
“MC3R links nutritional state to childhood growth and the timing of puberty.”
Authors: Lam, B.Y.H., Williamson, A., Finer, S. et al.