Regulatory T cells (Treg) play essential roles in maintaining immune homeostasis. Resident Treg in visceral adipose tissue (VAT-Treg) decrease in male obese mice, which leads to the development of obesity-associated chronic inflammations and insulin resistance. Although gender differences in immune responses have been reported, the effects of the difference in metabolic environment on VAT-Treg are unclear. We investigated the localization of VAT-Treg in female mice in comparison with that in male mice. On a high-fat diet (HFD), VAT-Treg decreased in male mice but increased in female mice. The increase was abolished in ovariectomized and HFD-fed mice, but was restored by estrogen supplementation. The IL33 receptor ST2, which is important for the localization and maturation of VAT-Treg in males, was reduced in CD4 + CD25 + T cells isolated from gonadal fat of obese mice of both genders, suggesting that a different system exists for VAT-Treg localization in females. Extensive analysis of chemokine expression in gonadal fat and adipose CD4 + CD25 + T cells revealed several chemokine signals related to female-specific VAT-Treg accumulation such as CCL24, CCR6, and CXCR3. Taken together, the current study demonstrated sexual dimorphism in VAT-Treg localization in obese mice. Estrogen may attenuate obesity-associated chronic inflammation partly through altering chemokine-related VAT-Treg localization in females.

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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.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a treatment-responsive encephalitis associated with anti-NMDAR antibodies. Unlike classic paraneoplastic encephalitis, this disorder usually develops in young women with ovarian teratoma who typically present with marked neuropsychiatric symptoms, followed by prolonged respiratory failure, clouding of consciousness, and bizarre dyskinesia. This disorder is often treatable by resection of ovarian tumor and immunotherapy, but, delayed diagnosis results in a worse condition and sometimes fatal outcome. However, some gynecologists are not familiar with this disorder. When physicians encounter a female patient with encephalitis showing marked neuropsychiatric symptoms, search for an ovarian tumor should be promptly initiated. We present a case of anti-NMDAR encephalitis associated with ovarian immature teratoma. The symptoms were dramatically relieved by tumor resection and immunotherapy.

A decrease in serum estrogen levels in menopause is closely associated with the development of visceral obesity and the onset of type 2 diabetes in women. In the present study, we demonstrated the therapeutic effects of the novel DPP4 inhibitor, teneligliptin, on the features of postmenopausal obesity in mice. In the control group, female C57BL/6 mice were sham-operated and maintained on a standard diet. In the postmenopausal obese group, ovariectomized (OVX) mice were maintained on a high-fat diet, and were referred to as OVX-HF. In the treated group, teneligliptin at 60 mg/kg per day was administrated to OVX-HF, and were referred to as Tene. After a 12-week food challenge, the metabolic phenotypes of these mice were analyzed. Body weight, fat accumulation, and glucose intolerance were greater in OVX-HF than in control, while these abnormalities were markedly improved without alterations in calorie intake in Tene. Teneligliptin effectively ameliorated the characteristics of metabolic abnormalities associated with postmenopausal obesity. Regarding chronic inflammation in visceral adipose tissue, the numbers of F4/80K M1-macrophages in flow cytometry, crown-like structure formation in immunohistochemistry, and proinflammatory cytokine expression were significantly attenuated in Tene. Hepatic steatosis was also markedly improved. Furthermore, decreased energy consumption in the dark and light phases, reduced locomotor activity in the dark phase, and lowered core body temperature in OVX-HF were ameliorated in Tene. Since obesity and reduced energy metabolism are a common physiology of menopause, teneligliptin appears to be beneficial as a treatment for type 2 diabetes in postmenopausal obesity. Key Words" dpp4 inhibitor " adipose tissue macrophage " energy expenditure " insulin resistance