title: Prevention of obesity and insulin resistance by estrogens requires ERα activation function-2 (ERαAF-2), whereas ERαAF-1 is dispensable.
abstract: The beneficial metabolic actions of estrogen-based therapies are mainly mediated by estrogen receptor α (ERα), a nuclear receptor that regulates gene transcription through two activation functions (AFs): AF-1 and AF-2. Using mouse models deleted electively for ERαAF-1 (ERαAF-1°) or ERαAF-2 (ERαAF-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). ERαAF-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 ERα protein (ERα(-/-)). In striking contrast, ERαAF-1° and wild-type (wt) mice shared a similar metabolic phenotype. Accordingly, 17β-estradiol administration regulated key metabolic genes in insulin-sensitive tissues and conferred a strong protection against HFD-induced metabolic disturbances in wt and ERαAF-1° ovariectomized mice, whereas these actions were totally abrogated in ERαAF-2° and ERα(-/-) 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 ERαAF-2 but not ERαAF-1, thereby delineating new options for selective modulation of ERα.
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université Toulouse III, Toulouse, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Handgraaf
authors.forename: Elodie
authors.initials: E
authors.lastname: Riant
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fabre
authors.forename: Aurélie
authors.initials: A
authors.lastname: Waget
authors.forename: Rémy
authors.initials: R
authors.lastname: Burcelin
authors.forename: Philippe
authors.initials: P
authors.lastname: Lière
authors.forename: Andrée
authors.initials: A
authors.lastname: Krust
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
authors.forename: Pierre
authors.initials: P
authors.lastname: Gourdy
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018149:Glucose Intolerance / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D001786:Blood Glucose; D047628:Estrogen Receptor alpha; D007328:Insulin; D004958:Estradiol
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