Scientists have recently proposed that obesity is a neurodevelopmental disorder.
Over the last several decades, obesity has rapidly grown to affect more than 2 billion people, making it one of the biggest contributors to poor health globally. Many individuals still have trouble losing weight despite decades of study on diet and exercise regimens. Researchers from Baylor College of Medicine and affiliated institutions now believe they understand why, and they argue that the emphasis should be shifted from treating obesity to preventing it.
The research team reports in the journal Science Advances that early-life molecular processes of brain development are likely a major determinant of obesity risk. Previous large human studies have shown that the genes most strongly associated with obesity are expressed in the developing brain. This most recent study in mice focused on epigenetic development. Epigenetics is a molecular bookmarking system that regulates whether genes are utilized or not in certain cell types.
“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,” said corresponding author Dr. Robert Waterland, professor of pediatrics-nutrition and a member of the USDA Children’s Nutrition Research Center at Baylor. “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,” said first author Dr. Harry MacKay, who was a postdoctoral associate in the Waterland lab while working on the project. “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.”
The researchers performed genome-wide analyses of gene expression and DNA methylation, a key epigenetic tag, before and after the postnatal critical window for the developmental programming of body weight closed.
“One of our study’s biggest strengths is that we studied the two major classes of brain cells, neurons, and glia,” MacKays said. “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 said. “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.”
The human connection
The biggest surprise came when the investigators compared their epigenetic data in mice to human data from large genome-wide association studies that screen for genetic variants associated with obesity. The genomic regions targeted for epigenetic maturation in the mouse arcuate nucleus overlapped strongly with human genomic regions associated with body mass index, an index of obesity.
“These associations suggest that obesity risk in humans is determined in part by epigenetic development in the arcuate nucleus,” MacKay said. “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.”
Reference: “Sex-specific epigenetic development in the mouse hypothalamic arcuate nucleus pinpoints human genomic regions associated with body mass index” by Harry MacKay, Chathura J. Gunasekara, Kit-Yi Yam, Dollada Srisai, Hari Krishna Yalamanchili, Yumei Li, Rui Chen, Cristian Coarfa and Robert A. Waterland, 28 September 2022, Science Advances.