Prevention of Obesity and Insulin Resistance by Estrogens Requires ERa Activation Function-2 ( ERαAF-2), Whereas ERαAF-1 Is Dispensable

The beneficial metabolic actions of estrogen-based therapies are mainly mediated by estrogen receptor (ER), a nuclear receptor that regulates gene transcription through two activation functions (AFs): AF-1 and AF-2. Using mouse models deleted electively for ERAF-1 (ERAF-1 degrees) or ERAF-2 (ERAF-2 degrees), we determined their respective roles in the actions of estrogens on body composition and glucose homeostasis in response to either a normal diet or a high-fat diet (HFD). ERAF-2 degrees males and females developed accelerated weight gain, massive adiposity, severe insulin resistance, and glucose intolerancequite reminiscent of the phenotype observed in mice deleted for the entire ER protein (ER-/-). In striking contrast, ERAF-1 degrees and wild-type (wt) mice shared a similar metabolic phenotype. Accordingly, 17-estradiol administration regulated key metabolic genes in insulin-sensitive tissues and conferred a strong protection against HFD-induced metabolic disturbances in wt and ERAF-1 degrees ovariectomized mice, whereas these actions were totally abrogated in ERAF-2 degrees and ER-/- mice. Thus, whereas both AFs have been previously shown to contribute to endometrial and breast cancer cell proliferation, the protective effect of estrogens against obesity and insulin resistance depends on ERAF-2 but not ERAF-1, thereby delineating new options for selective modulation of ER.