Obesity can be a neurodevelopmental disorder

Summary: Obesity is determined, in part, by the epigenetic development of the arcuate nucleus of the hypothalamus. The results suggest that developmental epigenetics play an important role in both environmental and genetic influences on obesity risk.

Source: Baylor College of Medicine

Obesity has risen rapidly in recent decades to affect more than 2 billion people, making it one of the biggest contributors to ill health worldwide. Despite decades of research into diet and exercise treatments, many people still struggle to lose weight.

Researchers at Baylor College of Medicine and partner institutions now think they know why, and say we need to shift the focus from obesity treatment to prevention.

The team reports to the newspaper Advances in Science that the molecular mechanisms of brain development during the first years of life are probably an important determinant of obesity risk.

Previous large studies in humans have suggested that the genes most strongly associated with obesity are expressed in the developing brain.

This current study in mice focused on epigenetic development. Epigenetics is a system of molecular markers that determine which genes will or will not be used in different types of cells.

“Decades of research in humans and animal models have shown that environmental influences during critical periods of development have an important long-term impact on health and disease,” said corresponding author Dr. Robert Waterland, professor of pediatrics-nutrition and member of the USDA Child Nutrition Research Center at Baylor.

“Body weight regulation is highly sensitive to this ‘developmental programming,’ but exactly how it works is still 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 Waterland’s lab. while working on the project.

“We found that the arcuate nucleus undergoes extensive epigenetic maturation during early postnatal life. This period is also exquisitely sensitive to the developmental programming of body weight regulation, suggesting that these effects could be a consequence of epigenetic maturation deregulated”.

The team performed genome-wide analyzes of both DNA methylation, an important epigenetic tag, and gene expression both before and after the close of the critical postnatal window for programming weight development bodily

“One of the main strengths of our study is that we studied the two main 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,” said Waterland.

Previous large studies in humans have suggested that the genes most strongly associated with obesity are expressed in the developing brain. The image is in the public domain

“We were surprised to find large sex differences. In fact, when it comes to these postnatal epigenetic changes, men and women are more different than similar. And, many of the changes occurred earlier in women than in men, which indicates that women are precocious in this regard.”

The human connection

The biggest surprise came when the researchers compared their epigenetic data in mice with human data from genome-wide association studies that detect genetic variants associated with obesity.

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 are likely involved in early environmental and genetic influences on obesity risk. Consequently, prevention efforts targeting these developmental processes could be the key to stopping the global obesity epidemic”.

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Other contributors to this work are Chathura J. Gunasekara, Kit-Yi Yam, Dollada Srisai, Hari Krishna Yalamanchili, Yumei Li, Rui Chen, and Cristian Coarfa. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Vanderbilt University, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, and Baylor’s Dan L Duncan Comprehensive Cancer Center.

About this research news on genetics, neurodevelopment and obesity

Author: Press Office
Source: Baylor College of Medicine
Contact: Press Office – Baylor College of Medicine
Image: The image is in the public domain

Original Research: Open access
“Sex-specific epigenetic development in the mouse hypothalamic arcuate nucleus identifies human genomic regions associated with body mass index” by Harry MacKay et al. Advances in Science


Sex-specific epigenetic development in the mouse hypothalamic arcuate nucleus identifies human genomic regions associated with body mass index

Recent genome-wide association studies corroborate classic developmental programming research indicating that obesity is primarily a neurodevelopmental disease strongly influenced by nutrition during critical ontogenic windows.

Epigenetic mechanisms regulate neurodevelopment; however, little is known about its role in establishing and maintaining brain energy balance circuits.

We generated methylomes and transcriptomes of neurons and glia from the male and female mouse hypothalamic arcuate nucleus, a key site for the regulation of energy balance, at times spanning the closing of an established critical window for developmental programming of the risk of obesity.

We find that postnatal epigenetic maturation is markedly cell-type and sex-specific and occurs in genomic regions enriched for the heritability of body mass index in humans.

Our results offer a potential explanation for both the limited ontogenic windows and sex differences in sensitivity to developmental programming in obesity and provide a rich resource for epigenetic analyzes of developmental programming in the ‘energy balance.

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