When it comes to fat accumulation, men tend to carry more weight around their abdomens (apple-shaped) while women tend to carry more weight around their hips and thighs (pear-shaped), but the mechanical reason for the difference has remained a mystery.

The apple-shaped body has been associated with higher risk of developing metabolic syndrome, largely because of increased accumulation of visceral fat around the waist (i.e., abdominal visceral fat).  

A team of Virginia Tech researchers has found that a fat cell remodeling (termed as autophagy) pathway was regulated by an estrogen receptor (ERa), which sits on the cell membrane and played a major role in the difference among men and women when it comes to fat build-up. The study, led by Zhiyong Cheng, an assistant professor of human nutrition, food and exercise in the College of Agriculture and Life Sciences, was recently published in the journal Cell Death and Disease.    

Cheng and his team showed that, in wild-type control mice, males had a higher visceral fat mass than females, and this is associated with higher cellular remodeling activity but lower expression of ERa in the males. However, deleting ERa in mice abolished the sex difference.

As a hormone receptor for the sex steroid 17β-estradiol, ERa is known to play an important role in sexual maturation and gestation. This study provides evidence to a new role of ERa in cellular remodeling and fat cell formation, i.e., 17β-estradiol-ERa signaling as a suppressor of fat cell remodeling and formation. Ablation or inhibition of ERa removes the brake on cellular remodeling and promotes fat cell formation, a process that may increase adiposity.

“Our results highlight the importance of considering sex difference in biomedical research and also shed light on why breast cancer patients who receive treatment in the form of estrogen receptor inhibitors may find that they gain visceral fat directly after treatment,” said Cheng, who is affiliated with the university’s Fralin Life Science Institute.

Two people looking at a sheet in a lab.
Zhiyong Cheng (left) works with a student.

Cheng has a long-standing research interest in obesity and metabolic alterations. Sex-dependent variation in the risks of metabolic diseases has been increasingly recognized, while the mechanism is poorly understood. “Given that accumulation of visceral fat increases the risks of developing metabolic diseases, we are interested in the molecular and cellular mechanisms of sex difference in visceral fat accumulation," he said.

“This study unravels a novel role of estrogen in women’s health by regulating autophagy, ” added Dongmin Liu, a professor of human nutrition, food, and exercise in the College of Agriculture and Life Sciences. “Because lifestyle factors influence estradiol homeostasis and age of natural menopause, lifestyle-targeting interventions may improve women’s metabolic health through the estradiol-autophagy pathway identified in this study,” said Fabio Almeida, who is an associate professor at University of Nebraska Medical Center.

Visceral fat is a conglomeration of small, tightly compacted cells that are less expandable but more prone to release fatty acid and pro-inflammatory factors contributing to insulin resistance in peripheral tissues like liver and skeletal muscle. These leaks can result in numerous health problems, such as increased risk for cardiovascular disease and type 2 diabetes.

Subcutaneous fat consists of larger, more flexible cells that have higher capacity to uptake and store excess fat and thereby are protective to vital organs. 

The research was funded by the U.S. Department of Agriculture/National Institute of Food and Agriculture (USDA/NIFA) and National Institutes of Health (NIH).

Co-authors include Dongmin Liu, a professor of human nutrition, foods, and exercise; first author Zhipeng Tao, a doctoral student in Cheng’s lab; Louise Zheng, research associate in Cheng’s lab; Cayleen Smith, former undergraduate in the Department of Biological Sciences; Jing Luo, a doctoral student in Liu’s lab; Alex Robinson, a undergraduate in the Department of Biological Sciences; Fabio Almeida, an associate professor at the University of Nebraska Medical Center; and Zongwei Wang and Aria Olumi, from with the Department of Urology at Harvard Medical School.

Written by Lindsay Key

Share this story