The National Institutes of Health (US), the UK Medical Research Council, Wellcome, and the National Institute for Health Research (UK) funded the study, which discovered how a protein on the brain uses information regarding the energy balance of the body to regulate the onset of puberty and growth rate in children.

The study, which will be published in the journal Nature on November 3rd, focuses on the melanocortin-3 receptor (MC3R), a member of a protein family that has long been known to be important in energy balance and metabolism.

How did the research on the MC3R gene go?

More than two decades ago, Roger Cone, a physiologist at the University of Michigan, and his colleagues discovered the gene called MC3R and demonstrated that mice that were lacking the protein have slower linear growth, a lower body mass index, and are more obese. Cone’s group’s subsequent research has also shown that the receptor plays a role in regulating the interplay between reproduction and energy status, including weight gain and diet  during pregnancy.

Scientists from all over the world directed by Sir Stephen O’Rahilly of the Wellcome-MRC Institute of Metabolic Science at the University of Cambridge have now disclosed for the first time how the gene MC3R defects manifest in humans, with results that are strikingly similar to those discovered in mice.

Using data from the Avon Longitudinal Study of Parents and Children and UK Biobank, the researchers looked at the phenotypes of volunteers who had mutations in one copy of the MC3R gene. When compared to people who do not have MC3R mutations, these people have shorter stature and a lower BMI.

What was the outcome of this study on the MC3R genes?

O’Rahilly’s team has identified the first person who has mutations in both copies of the MC3R gene, rendering the person inoperable. Such incidents are extremely rare, occurring in only one person in a million. This person had phenotypes, or physical characteristics, that were nearly identical to mice lacking the MC3R gene.

Cone, one of the study’s authors and the director of the University of Michigan Life Sciences Institute, stated: “In terms of melanocortins, every phenotype that we have observed in the mouse has ultimately been found to be replicated in humans,” adding that “This direct correlation between animal models and humans is not always the case, but this research shows that mice are a near-perfect model for studying human syndromes related to melanocortin receptors.”

Furthermore, O’Rahilly discovered a new phenotype in people with MC3R gene mutations, as they discovered subtle but significant delays in UK Biobank volunteers with a single copy of the gene and a significant delay in the onset of puberty in the MC3R deficient patient. As only one patient had lost two copies of the MC3R gene, the researchers used knock-out mouse models to better understand and confirm the results.

The current data, published in this study by Cone’s lab and collaborator Richard Simerly at Vanderbilt School of Medicine, suggest that MC3R plays a role in communicating nutritional deficiencies to the reproductive axis and also confirm this effect.

When mice spend 24 hours together, the MC3R identifies a lack of energy reserves in the body and sends this information to the brain part that regulates reproductive cycles. Normal mice’s reproductive cycles halt until their energy reserves return to normal, which occurs after fasting. However, in mice lacking the MC3R gene, no change in the reproductive axis is observed after fasting, meaning that communication on energy balance has ceased.

“These types of experiments give us an important new understanding of the body’s metabolic and reproductive pathways, but they obviously cannot be done in humans,” said Cone, who is also integrative physiology at the U-M Medical School and a professor of molecular biology. “This research illustrates the critical role of animal models for studying the fundamentals of physiology, which can then be translated to human health and disease.”

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