Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance

Purpose: Obesity increases the risk of diabetes. The dysregulation of estrogen metabolism has been associated with the susceptibility to obesity and diabetes. Here, we explore the role estrogen plays in sex differences in obesity and glucose metabolism, specifically adipocyte biology. Methods: We randomized C57BL/6 J male, non-ovariectomized female, ovariectomized female, and ovariectomized female mice supplemented with 17β estradiol to receive a calorie-restricted, low- or a high-fat diet (15 mice per group). We measured weight gained, calories consumed, percent body fat, abdominal adipose tissue, adipocyte size, lipogenic and adipogenic gene expression, and glucose tolerance. Results: Male mice had a higher susceptibility to obesity than intact female mice. However, removal of the ovaries in female mice eliminated the protection to obesity and estrogen supplementation restored this protection. Male and ovariectomized female mice gained weight predominately in the form of abdominal adipose tissue possibly due to an increase in adipocyte size. Moreover, for mice consuming the high-fat diet, male and ovariectomized female mice had significantly higher levels of leptin mRNA and lower hormone-sensitive lipase mRNA relative to intact female mice and ovariectomized female mice supplemented with estrogen. Additionally, estrogen had a strong inhibitory effect on key adipogenic genes in non-ovariectomized female and ovx-female mice supplemented with estrogen. Finally, we show that male and ovariectomized female mice consuming the high-fat diet had a higher incidence of glucose intolerance. Conclusion: Estrogen protects female mice from obesity and impaired glucose tolerance possibly by modulating the expression of genes regulating adipogenesis, lipogenesis, and lipolysis.