Prevention of obesity and insulin resistance by estrogens requires era activation function-2 (ERaAF-2), whereas ERaAF-1 is dispensable

Abstract

The beneficial metabolic actions of estrogen-based therapies are mainly mediated by estrogen receptor a (ERa), a nuclear receptor that regulates gene transcription through two activation functions (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 phenotype observed in mice deleted for the entire ERa protein (ERa2/2). In striking contrast, ERaAF-1 and wild-type (wt) mice shared a similar metabolic phenotype. Accordingly, 17b-estradiol administration regulated key metabolic genes in insulin-sensitive tissues and conferred a strong protection against HFD-induced metabolic disturbances in wt and ERaAF-1 ovariectomized mice, whereas these actions were totally abrogated in ERaAF-2 and ERa2/2 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 ERaAF-2 but not ERaAF-1, thereby delineating new options for selective modulation of ERa. © 2013 by the American Diabetes Association.