Central versus peripheral impact of estradiol on the impaired glucose metabolism in ovariectomized mice on a high-fat diet

Age-related loss of ovarian function promotes adiposity and insulin resistance in women. Estrogen (E2) directly enhances insulin sensitivity and suppresses lipogenesis in peripheral tissues. Recently, the central actions of E₂ in the regulation of energy homeostasis are becoming clearer; however, the functional relevance and degree of contribution of the central vs. peripheral actions of E₂ are currently unknown. Therefore, we prepared and analyzed four groups of mice. 1) Control: shamoperated mice fed a regular diet, 2) OVX-HF: ovariectomized (OVX) mice fed a 60% high-fat diet (HF), 3) E2-SC: OVX-HF mice subcutaneously treated with E₂, and 4) E2-ICV: OVX-HF mice treated with E₂ intracerebroventricularly. OVX-HF mice showed increased body weight with both visceral and subcutaneous fat volume enlargement, glucose intolerance, and insulin resistance. Both E2-SC and E2-ICV equally ameliorated these abnormalities. Although the size of adipocytes and number of CD11c-positive macrophages in perigonadal fat in OVX-HF were reduced by both E₂ treatments, peripherally administered E₂ decreased the expression of TNFα, lipoprotein lipase, and fatty acid synthase in the white adipose tissue (WAT) of OVXHF. In contrast, centrally administered E₂ increased hormone-sensitive lipase in WAT, decreased the hepatic expression of gluconeogenic enzymes, and elevated core body temperature and energy expenditure with marked upregulation of uncoupling proteins in the brown adipose tissue. These results suggest that central and peripheral actions of E2 regulate insulin sensitivity and glucose metabolism via different mechanisms, and their coordinated effects may be important to prevent the development of obesity and insulin resistance in postmenopausal women.