Impact of central and peripheral estrogen treatment on anxiety and depression phenotypes in a mouse model of postmenopausal obesity

Obesity and diabetes increase the risk of depression, and the incidence of these conditions increases rapidly after menopause, but few animal models of postmenopausal obesity have been available. We developed a mouse model of postmenopausal obesity that exhibited anxiety and depressive phenotypes in behavioral tests. To examine the effect of estradiol (E2) in the model, we prepared 4 experimental groups: 1) control, sham-operated female C57BL/6 mice fed a regular diet; 2) OVX-HF, ovariectomized (OVX) mice fed a high-fat diet (HF); 3) E2-SC, OVX-HF mice administered subcutaneous (SC) E2 (50 μg/kg/day); and 4) E2-ICV, OVX-HF mice administered intracerebroventricular (ICV) E2 (1 μg/kg/day). OVX-HF mice exhibited anxiety phenotypes in the open field test, but not in the light-dark box test, and E2 treatment via both routes effectively ameliorated it. OVX-HF mice demonstrated depressive phenotypes in the tail suspension test and forced swim test. Both E2 treatments achieved significant improvement in the tail suspension test, but not in the forced swim test. Serum corticosterone levels did not differ among the groups. Hippocampal expression of glucocorticoid receptor mRNA and serotonin 1A receptor mRNA was significantly increased in OVX-HF mice and was decreased in E2-treated mice. The hypothalamic level of pro-brain-derived neurotrophic factor (proBDNF) protein was tended to decrease in OVX-HF mice, but neither E2 treatment increased it. Since this mouse model exhibited anxiety and depressive phenotypes in relatively short experimental periods without genetic manipulations, it would be useful for further exploring psychiatric phenotypes or screening of therapeutic candidates in postmenopausal obesity.