Over the past few decades, obesity has rapidly expanded to affect more than 2 billion people, making it one of the biggest causes of ill health globally. Many people still have trouble losing weight despite decades of research on diets and exercise regimens. Now that they believe they know why, scientists from Baylor College of Medicine and other institutions argue that prevention should take precedence over obesity treatment.
The research team claims in the journal Science Advances that early-life molecular mechanisms of brain development are probably a significant factor in the risk of obesity. Large human research conducted in the past has suggested that the developing brain expresses the genes most strongly linked to obesity. Epigenetic development was the main focus of the most recent mouse study. Epigenetics is a molecular bookmarking system that controls which genes are used or not in certain cell types.
Dr. Robert Waterland, professor of pediatrics-nutrition and a member of the USDA Children’s Nutrition Research Center at Baylor, said, “Decades of research in humans and animal models has shown that environmental influences during critical periods of development have a major long-term impact on health and disease.” Even though nobody knows how this “developmental programming” works, it has a big effect on how the body controls its weight.
Dr. Harry MacKay, the study’s first author and a postdoctoral assistant in the Waterland lab at the time, said, “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.” We found that early postnatal life involves significant epigenetic maturation in the arcuate nucleus. It is possible that these effects are a result of dysregulated epigenetic maturation during this era because it is also exceptionally sensitive to developmental programming of body weight management. ”
The team performed genome-wide assessments of gene expression and DNA methylation, two crucial epigenetic tags, both before and after the postnatal critical window for the developmental programming of body weight closed. According to MacKays, the fact that we looked at the two main groups of brain cells, neurons and glia, is one of the study’s strongest points. It turns out that these two cell types’ epigenetic maturation are significantly distinct from one another.
According to Waterland, “our work is the first to compare this epigenetic development in males and girls.” “We were shocked to discover significant sex disparities. In actuality, males and females differ more from one another than they resemble in terms of these postnatal epigenetic modifications. Additionally, a lot of the alterations happened in females far sooner than in males, showing that females are precocious in this area.
The human connection
The biggest shock was discovered when the researchers compared their mouse epigenetic data to human data from extensive genome-wide association studies that looked for genetic variations linked to fat. The parts of the human genome that are linked to the body mass index, which is a way to measure obesity, were very similar to the parts of the mouse arcuate nucleus that are targeted for epigenetic maturation.
According to MacKay, these correlations imply that epigenetic changes in the arcuate nucleus play a role in human obesity risk. “Our findings offer further proof that early environmental and genetic influences on obesity risk likely include developmental epigenetics. Therefore, focusing preventative efforts on these developmental processes may be essential for putting an end to the global obesity pandemic. ”
Chathura J. Gunasekara, Kit-Yi Yam, Dollada Srisai, Hari Krishna Yalamanchili, Yumei Li, Rui Chen, and Cristian Coarfa are additional authors of this work. The authors are connected to one or more of the following organizations: the Dan L. Duncan Comprehensive Cancer Center at Baylor; Vanderbilt University; the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital; and Baylor College of Medicine.
Grants from the USDA (CRIS 3092-5-001-059), NIH (5R01DK111831, S10OD023469, CA125123, and 1159 RR024574), NIEHS (P30 ES030285), and CPRIT helped to fund this research (CPRIT-RP180672).
