Scientists find out how our brains use nutrients
Scientists have discovered how a receptor in the brain called MC3R detects the nutritional state of the body and regulates the time of puberty and the rate of growth in children and increases lean muscle mass.
These results, published today in the journal Nature, can explain how humans grew and reached sexual maturity earlier in the last century. During the 20th century, the average height increased by around 10cm in the UK and up to 8cm in other countries.
While scientists have long suggested that this phenomenon may be linked to more reliable access to food for pregnant women and children, so far the precise way the body perceives its nutritional status and turns that information into growth. and in sexual maturation had not been understood.
It was already known that signals reach the brain to indicate the nutritional state of the body, such as the hormones leptin, produced in adipose (fat) cells, and insulin, produced in response to increased blood sugar levels in the body. blood. In a part of the brain called the hypothalamus, these hormones act on a small group of neurons that produce signals called melanocortins.
Melanocortins act on a variety of receptors, two of which are found in the brain. One of them, the melanocortin 4 receptor (MC4R) has already been shown to regulate appetite and the lack of MC4R leads to obesity; however, the MC4R system does not control the effect of nutrition on growth and the timing of puberty.
Now a study, led by researchers from the MRC Metabolic Diseases Unit and the MRC Epidemiology Unit (both part of the Wellcome-MRC Institute of Metabolic Science) at the University of Cambridge, with collaborators from Queen’s University Mary of London, of the University of Bristol, University of Michigan and Vanderbilt University, discovered a role for the brain’s other melanocortin receptor, known as the melanocortin 3 receptor (MC3R).
They found that in response to nutritional cues, the MC3R system controls the release of key hormones that regulate growth and sexual maturation.
To show the link in humans, scientists searched the half-million UK Biobank volunteers for people with naturally-occurring genetic mutations that disrupt MC3R function. They identified a few thousand people who carried various mutations in the MC3R gene and found that these people were on average shorter and entered puberty later than those without the mutation.
For example, they identified 812 women who had the same mutation in one of their two copies of the MC3R gene. This mutation only partially reduced the receptor’s ability to function. Despite this subtle effect, women who carried it were on average 4.7 months longer to go through puberty than those who did not have the mutation.
People with mutations that reduced MC3R function were also shorter and had lower amounts of lean tissue, such as muscle, but this had no influence on the amount of fat they carried.
To confirm these findings in children, they studied nearly 6,000 participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) and identified six children with mutations in MC3R. All six children were smaller and had lower lean mass and weight throughout childhood, showing that this effect begins very early in life.
All of the people 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, but in another cohort, researchers were able to identify an individual in the Genes and Health study with a very damaging mutation in both copies of the gene. This person was very small and entered puberty after the age of 20.
This same phenomenon linking adequate body nutritional reserves to reproductive maturity is observed throughout the animal kingdom. The researchers therefore conducted studies in mice to confirm that the MC3R pathway works across species. Work in the laboratory of Dr. Roger Cone at the University of Michigan, who had previously demonstrated a role of MC3R in the control of growth and lean mass in mice, showed that if normal mice interrupt their reproductive cycle when they undergo a period of food deprivation, mice conceived to run out of MC3R did not. This confirmed that MC3R is a necessary part of how nutritional status controls the production of sex hormones.
Professor Sir Stephen O’Rahilly, lead author of the study and director of the MRC Metabolic Diseases Unit at Cambridge University, said: “This discovery shows how the brain can sense nutrients and interpret them to make subconscious decisions that influence our growth and sexual development. Identifying the pathway in the brain by which nutrition turns into growth and puberty explains a worldwide phenomenon of heightening and decreasing age at puberty that has puzzled scientists for a century.
“Our results have immediate practical implications for screening for MC3R mutations in children with severe delays in growth and pubertal development.
“This research may have broader implications beyond child development and reproductive health. Many chronic diseases are associated with the loss of lean mass, especially muscle, resulting in fragility. It responds poorly to simple nutritional supplements such as high protein drinks. The finding that MC3R pathway activity influences the amount of lean mass a person carries suggests that future research should determine whether drugs that selectively activate MC3R could help redirect calories to muscle and other lean tissue in the body. prospect of improving physical functioning. of these patients.
Professor John Perry, lead author of the study from Cambridge University’s MRC Epidemiology Unit, said: “These are such an exciting times for human genetics. By analyzing the genetic sequences of a large number of research participants, we can now understand fundamental biological processes that have remained elusive until now. By combining these studies with experiments in cell and animal models, we will continue to uncover new knowledge and understand the mechanisms underlying human growth and metabolic disease. “
The research was funded by the UK Medical Research Council, Wellcome and the National Institute for Health Research.
Dr Rob Buckle, Scientific Director of the Medical Research Council, which funded the research, said: Of those who suffer from frailty caused by chronic diseases. This study shows the value of long-term investment in large cohorts of the UK population and in multidisciplinary research to uncover the underlying causes of human health and disease. “
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MC3R links nutritional status to child growth and the time of puberty
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