New Insights Into Metabolic Regulation via Bifurcated Function of Estrogen Receptor α

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Estrogen plays multifunctional roles in the regulation of human physiology, including sexual function and reproduction, immunity, neural function, bone metabolism, and energy homeostasis (1,2). Although clinical trials demonstrated the beneficial effect of estrogen supplementation on glucose and lipid metabolism in menopausal women (3,4), hormone replacement therapy to improve metabolism is not practical because of the possible risk for estrogen-dependent malignancies and cardiovascular disease. Recent reports have indicated that there are at least three functional estrogen receptors: the classical nuclear estrogen receptor α (ERα) and β (ERβ), and the endoplasmic reticulum-localized G protein–coupled receptor GPR30 (5,6). Studies using genetic knockout mice revealed the functional differences of these receptors on the distinct actions of estradiol (E2). Accumulating evidence indicates that ERα plays a predominant role in regulation of glucose and lipid metabolism (2,7–11). For instance, myeloid-specific ERα knockout mice showed obesity and adipose tissue inflammation with insulin resistance (7). Treatment with estrogen failed to improve high-fat diet (HFD)–induced insulin resistance and fatty liver in hepatocyte-specific ERα knockout mice (8). More recently, E2 has emerged as a central regulator of both energy metabolism and physical activity (9–11). Central effects of E2 were sufficient to increase energy expenditure and physical activity, suppress the expression of hepatic gluconeogenic genes, and reduce fat volume …