MC3R Links Nutritional Status to Child Growth and Pubertal Timing

Scientists have determined how a protein in the brain uses information about the body's energy balance to regulate children's growth rate and the onset of puberty.

The study focuses on the melanocortin 3 receptor (MC3R), a member of the protein family, which has long been thought to play an important role in metabolism and energy balance.

Roger Cone, a physiologist at the University of Michigan, and colleagues discovered the MC3R gene more than 20 years ago and demonstrated reduced linear growth in mice lacking this protein. Subsequent studies published by Cone's group have also shown that this receptor plays a role in regulating the interaction between reproductive and energy status, including increased eating and weight gain during pregnancy.

Now, an international team of scientists led by Stephen O'Rahilly of the Institute for Metabolic Sciences at the University of Cambridge has revealed for the first time how defects in MC3R translate into humans—results that are strikingly similar to findings in mice.

The O'Rahilly team reported the first person to have a mutation in both copies of the MC3R gene, which made his MC3R nonfunctional. Such cases are extremely rare and may occur in a billion people only. The phenotype or physiological characteristics exhibited by this individual were nearly identical to those of mice without MC3R.

Using data from the UK Biobank and the Children's Longitudinal Study, the team analyzed the phenotype of a copy of the MC3R-encoding gene mutated in volunteers. These individuals showed shorter height and less lean mass compared to those without MC3R mutations.

"In terms of melanocortin, every phenotype we observe in mice is eventually found to be replicated in humans," says Cone. "The direct link between animal models and humans is not always the case. But this study shows that mice are a near-perfect model for studying the human syndrome associated with the melanocortin receptor."

In addition, O'Rahilly found a new phenotype in people with MC3R mutations: in patients lacking MC3R, there was a long delay in the onset of puberty, while in volunteers at the UK Biobank, only a copy of the gene was mutated. Since only two copies of the MC3R gene were found to be lost in one patient, the researchers also used a mouse knockout model to confirm and further understand the findings.

New data generated by Richard Simely, a collaborator of Cone Lab and Vanderbilt Medical School, published in this latest study, confirms this effect and believes that MC3R plays a role in conveying nutrient deprivation to the reproductive axis.

When the mice fasted for 24 hours, MC3R detected insufficient energy storage in the body and relayed the information to the part of the brain responsible for regulating the reproductive cycle. In normal mice, the reproductive cycle stops until energy reserves return to normal, that is, after fasting. However, in mice without MC3R, the reproductive axis did not change after fasting, indicating that communication about energy balance has ceased.

"These types of experiments give us important new insights into the human body's metabolism and reproductive pathways, but obviously they cannot be performed on humans," Cone said. "This research illustrates the key role of animal models in the scientific foundation of graduate students, and this basic research can be transformed into human health and disease research."