Fiche publication
Date publication
décembre 2013
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre
Tous les auteurs :
Handgraaf S, Riant E, Fabre A, Waget A, Burcelin R, Liere P, Krust A, Chambon P, Arnal JF, Gourdy P
Lien Pubmed
Résumé
The beneficial metabolic actions of estrogen-based therapies are mainly mediated by estrogen receptor alpha (ERalpha), a nuclear receptor that regulates gene transcription through two activation functions (AFs): AF-1 and AF-2. Using mouse models deleted electively for ERalphaAF-1 (ERalphaAF-1 degrees ) or ERalphaAF-2 (ERalphaAF-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). ERalphaAF-2 degrees 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 ERalpha protein (ERalpha(-/-)). In striking contrast, ERalphaAF-1 degrees and wild-type (wt) mice shared a similar metabolic phenotype. Accordingly, 17beta-estradiol administration regulated key metabolic genes in insulin-sensitive tissues and conferred a strong protection against HFD-induced metabolic disturbances in wt and ERalphaAF-1 degrees ovariectomized mice, whereas these actions were totally abrogated in ERalphaAF-2 degrees and ERalpha(-/-) 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 ERalphaAF-2 but not ERalphaAF-1, thereby delineating new options for selective modulation of ERalpha.
Référence
Diabetes. 2013 Dec;62(12):4098-108
