P3-09-05: Understanding the Role of Estrogen in Sex Differences in Adipocyte Biology for Cancer Prevention.

Background: Evidence shows that obesity increases the risk and mortality of many cancers, specifically breast cancer in post-menopausal women. Epidemiological studies demonstrate that males are at an increased risk for developing obesity, diabetes, and cancer compared to females, and after menopause, females mimic the males in their susceptibility to the above diseases. Furthermore, it has been established that obesity increases systemic and adipose tissue inflammation and oxidative stress, which is known to augment cancer progression. However, the role of estrogen in regulating these metabolic processes in adipose tissue is unclear; therefore, our objective is to determine the role of estrogen in adipose tissue morphology, inflammation and oxidative stress. Methods: To determine the role of estrogen in gender differences in the susceptibility to obesity we used C57BL/6J mice (15/group): 1) males 2) nonovariectomized females 3) ovariectomized females and 4) ovariectomized females supplemented with estrogen, which were randomized to the following diets: 30% calorie-restricted, low-fat or high-fat diet. We measured weight gain, percent body fat, abdominal adipose tissue, and adipocyte size. Additionally, we assessed markers of adipose tissue inflammation, DNA damage, and oxidative stress. Results: Male mice were more susceptible to obesity than female mice. Removal of the ovaries eliminated the protection to obesity and estrogen supplementation restored this protection in females. In the low-fat and high-fat diet groups, male and ovariectomized female mice gained more abdominal adipose tissue due to increased adipocyte size compared to nonovariectomized female mice and ovariectomized female mice supplemented with estrogen. In the mice consuming the high fat diet, the enlarged adipocytes observed in the male and ovariectomized female mice were accompanied with crownlike structures surrounding necrotic adipocytes and F480 positive macrophages, suggesting macrophage infiltration. To determine if there were sex differences in oxidative stress, we stained adipose tissue with γH2AX. Results suggest that nonovariectomized female mice and ovariectomized female mice supplemented with estrogen have less oxidative stress compared to males and ovariectomized females. Additionally, our results show that nonovariectomized female and ovariectomized female mice supplemented with estrogen had significantly lower CD68, TNFα and iNOS mRNA expression levels, but higher catalase mRNA expression levels. Conclusion: Male mice are more susceptible to the obesogenic effects of high fat diets compared to nonovariectomized female mice. In ovariectomized females, estrogen supplementation has a protective effect against obesity, adipose tissue inflammation and oxidative stress. Our future studies will determine the mechanisms by which estrogen protects female mice from adipose tissue inflammation and oxidative stress, whether it is a direct or indirect effect. Determining the role of estrogen on the above key metabolic processes related to obesity is necessary to develop effective strategies for cancer prevention specifically in post-menopausal females. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-09-05.