Weight gain and the brain: Is obesity actually a neurodevelopmental disorder?

HOUSTON — Obesity is a widespread health issue, affecting more than two billion people globally. Studies continue to show that too much weight is one of the leading causes of chronic health problems — from diabetes to heart disease. Now, a new study finds obesity may have more to do with the brain than it does with someone's diet.

Researchers from the Baylor College of Medicine say that molecular mechanisms of early brain development likely play a key role in who ends up becoming obese. They add that previous studies have suggested that genes connected to obesity start expressing themselves in the developing brain after childbirth.

The new study looked at epigenetic development in mice, which is the system of molecular bookmarking that determines which genes are active in different cells.

“Decades of research in humans and animal models have shown that environmental influences during critical periods of development have a major long-term impact on health and disease,” says corresponding author Dr. Robert Waterland, a professor of pediatrics-nutrition and a member of the USDA Children’s Nutrition Research Center at Baylor, in a university release. “Body weight regulation is very sensitive to such ‘developmental programming,’ but exactly how this works remains unknown.”

“In this study we focused on a brain region called the arcuate nucleus of the hypothalamus, which is a master regulator of food intake, physical activity and metabolism,” adds first author Dr. Harry MacKay. “We discovered that the arcuate nucleus undergoes extensive epigenetic maturation during early postnatal life. This period is also exquisitely sensitive to developmental programming of body weight regulation, suggesting that these effects could be a consequence of dysregulated epigenetic maturation.”

Male and female brains develop differently

To uncover obesity's link to the growing brain, the team conducted a genome-wide analyses of both DNA methylation (an important epigenetic tag) and gene expression. They studied these processes both before and after a critical window in developmental programming for body weight among postnatal mice — meaning right after birth.

“One of our study’s biggest strengths is that we studied the two major classes of brain cells, neurons and glia,” MacKays explains. “It turns out that epigenetic maturation is very different between these two cell types.”

“Our study is the first to compare this epigenetic development in males and females,” Waterland says. “We were surprised to find extensive sex differences. In fact, in terms of these postnatal epigenetic changes, males and females are more different than they are similar. And, many of the changes occurred earlier in females than in males, indicating that females are precocious in this regard.”

To their surprise, the team discovered clear similarities between epigenetic data in mice and human genetic changes linked to obesity. Genomic regions targeted for epigenetic maturation in the mouse arcuate nucleus stunningly matched up with human brain regions connected to body mass index.

“These associations suggest that obesity risk in humans is determined in part by epigenetic development in the arcuate nucleus,” MacKay reports. “Our results provide new evidence that developmental epigenetics is likely involved in both early environmental and genetic influences on obesity risk. Accordingly, prevention efforts targeting these developmental processes could be the key to stopping the worldwide obesity epidemic.”

The study is published in the journal Science Advances.