Prevention of Obesity and Insulin Resistance by Estrogens Requires ERa Activation Function-2

The beneficial metabolic actions of estrogen-based therapies are mainly mediated by estrogen receptor a (ERa), a nuclear recep-tor that regulates gene transcription through two activation func-tions (AFs): AF-1 and AF-2. Using mouse models deleted electively for ERaAF-1 (ERaAF-1°) or ERaAF-2 (ERaAF-2°), 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). ERaAF-2 ° males and females developed accelerated weight gain, massive adiposity, severe insulin resistance, and glucose intolerance—quite reminiscent of the pheno-type observed in mice deleted for the entire ERa protein (ERa2/2). In striking contrast, ERaAF-1 ° and wild-type (wt) mice shared a sim-ilar metabolic phenotype. Accordingly, 17b-estradiol administration regulated key metabolic genes in insulin-sensitive tissues and con-ferred a strong protection against HFD-induced metabolic distur