SUN-474 Estradiol Protects Against High-Fat Diet-Induced Obesity and Anxiety in Female Mice

Abstract

Menopause is characterized by a decline in ovarian function and a decrease in estrogens. This decrease in estrogens leads to changes in metabolic phenotype, increasing the risk of weight gain from fat, metabolic syndrome, and type 2 diabetes in postmenopausal women. Menopause is also associated with changes in anxiety and mood. Estradiol (E) exerts similar metabolic effects in female mice as in women. We and others have shown that ovariectomized mice fed a high-fat diet (HFD) become obese, while mice treated with E remain lean. Furthermore, in female mice, HFD increases anxiety, and E acts in specific brain regions to influence anxiety and energy metabolism. However, the mechanisms by which E and diet interact to affect anxiety in females are not well understood. The present study tested the hypothesis that E protects against HFD-induced anxiety-like behavior by altering neural activity in brain regions involved in energy regulation and anxiety. Eight-week-old C57BL6J mice were ovariectomized and implanted with capsules containing either E (50 μg E in 25 μl of 5% ETOH/sesame oil) or vehicle (V). Within each treatment group, mice were fed a standard diet (SD) for 10 days and then maintained on SD or switched to HFD for 26 more days. Mice were weighed and food intake was measured every three days. Starting on day 30, anxiety-like behavior was assessed with three behavior tests: 1) light-dark 2) open-field and 3) elevated plus maze, with an interval of 3 days between each test. To investigate the effects of HFD and E on anxiety-induced neural activity, animals were perfused after the last behavior test. Whole brains were cleared, labeled and imaged for Fos using immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO). The V mice on HFD weighed at least 32% more than all other groups on day 36, while E mice remained lean and had reduced food intake, indicating that E protects against HFD-induced obesity. HFD increased anxiety behavior in the elevated plus maze test as HFD-fed mice spent less time in the open arms (p=0.03). E reduced anxiety-like behavior in mice fed a HFD as measured by the light-dark test. E mice on HFD spent more time in the light compartment than V mice on HFD (p=0.02). E decreased anxiety-like behavior in the open-field test, as E mice entered the center zone more times than V mice (p=0.048). Interestingly, in mice fed a HFD, E decreased Fos expression in the paraventricular hypothalamic nucleus (q<0.1), bed nucleus of the stria terminalis (q<0.05), and the subparafascicular area of the thalamus (q<0.001), suggesting that E protects against HFD-induced anxiety by decreasing neural activity in these specific brain regions. These findings provide insight into the potential mechanisms by which estrogens and diet interact to regulate energy homeostasis and anxiety in postmenopausal women. Work was funded by Otsuka Pharmaceutical Development & Commercialization, Inc.