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Brain receptor linked to puberty and growth

New findings shed light on the timing of puberty. Iren_Geo / Shutterstock

Children have been growing taller and reaching puberty earlier over the past century. It was thought that better nutrition was the likely cause. Studies have shown that the start of puberty is more related to body weight than to age.

The timing of puberty is controlled by neurons in the brain’s hypothalamus. The body sends signals to these neurons about its state of growth. The hypothalamus then releases hormones that trigger the start of puberty. But exactly how a child’s nutritional state affects the brain and impacts the onset of puberty wasn’t understood.

A research team led by scientists at the University of Cambridge explored the role of melanocortin receptors in the brain, which they suspected might be involved. Melanocortins are a group of hormones involved in appetite and food intake. There are two types of melanocortin receptors in the brain. Humans and mice that lack the melanocortin 4 receptor eat excessively and are obese, but there is no effect on growth or puberty onset. Thus, the researchers turned their attention to the role of the melanocortin 3 receptor, or MC3R.

The study was funded in part by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Findings appeared in Nature on November 3, 2021.

The team searched a genomic database for people with mutations that disrupted the function of the MC3R gene. Among the 500,000 volunteers, they found several thousand who carried such mutations. These individuals had a later onset of puberty. For example, women with the mutations had their first menstrual cycle an average of more than four months later than those without them. MC3R variants were also linked to shorter height, lower lean body mass, and low levels of a hormone involved in childhood growth.

The researchers next studied the effect of MC3R mutations among children. In a database of 6,000 participants, they found six children carrying mutations that cause disfunction in MCR3. All were shorter than average. The team then looked for people carrying two copies of the defective gene. They identified one man whose parents were second cousins. He was very short, had been overweight since childhood, and did not experience puberty until his 20s.

Additional experiments showed that mice lacking MC3R reached sexual maturity later. Food deprivation did not disrupt their reproductive cycle, as it does in other mice.

Taken together, the results suggest that MC3R plays an important role in influencing puberty and growth.

“This discovery shows how the brain can sense nutrients and interpret this to make subconscious decisions that influence our growth and sexual development,” says Dr. Stephen O’Rahilly of the University of Cambridge, a senior author of the study. “Identifying the pathway in the brain whereby nutrition turns into growth and puberty explains a global phenomenon of increasing height and decreasing age at puberty that has puzzled scientists for a century.”

The findings may open up new approaches to the diagnosis and management of disorders in children’s growth and sexual maturation.

—by Erin Bryant