Prevention of Obesity and Insulin Resistance by Estrogens Requires ERα Activation Function-2 (ERαAF-2), Whereas ERαAF-1 Is Dispensable
- Sandra Handgraaf1,
- Elodie Riant1,
- Aurélie Fabre1,
- Aurélie Waget1,
- Rémy Burcelin1,
- Philippe Lière2,
- Andrée Krust3,
- Pierre Chambon3,
- Jean-François Arnal1 and
- Pierre Gourdy1,4⇑
- 1INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université Toulouse III, Toulouse, France
- 2INSERM U788 and Université Paris-Sud 11, Le Kremlin-Bicêtre, France
- 3Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, INSERM, Université de Strasbourg, Collège de France, Illkirch, France
- 4Service de Diabétologie, Maladies Métaboliques et Nutrition, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
- Corresponding author: Pierre Gourdy, .
S.H. and E.R. contributed equally to this study.
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.
See accompanying commentary, p. 3996.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0282/-/DC1.
- Received February 27, 2013.
- Accepted July 26, 2013.
- © 2013 by the American Diabetes Association.
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