Prevention of obesity and insulin resistance by estrogens requires ER? activation function-2 (ER?AF-2), whereas ER?AF-1 is dispensable.

ABSTRACT: 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 ER?AF-1 (ER?AF-1°) or ER?AF-2 (ER?AF-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). ER?AF-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 ER? protein (ER?(-/-)). In striking contrast, ER?AF-1° 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 ER?AF-1° ovariectomized mice, whereas these actions were totally abrogated in ER?AF-2° 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 ER?AF-2 but not ER?AF-1, thereby delineating new options for selective modulation of ER?.

SUBMITTER: Handgraaf S 

PROVIDER: S-EPMC3837069 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature