Prevention of Obesity and Insulin Resistance by Estrogens Requires ERα Activation Function-2 (ERαAF-2), Whereas ERαAF-1 Is Dispensable

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°...

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Main Authors:	Handgraaf, Sandra, Riant, Elodie, Fabre, Aurélie, Waget, Aurélie, Burcelin, Rémy, Lière, Philippe, Krust, Andrée, Chambon, Pierre, Arnal, Jean-François, Gourdy, Pierre
Format:	Online
Language:	English
Published:	American Diabetes Association 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837069/

id	pubmed-3837069
recordtype	oai_dc
spelling	pubmed-38370692014-12-01 Prevention of Obesity and Insulin Resistance by Estrogens Requires ERα Activation Function-2 (ERαAF-2), Whereas ERαAF-1 Is Dispensable Handgraaf, Sandra Riant, Elodie Fabre, Aurélie Waget, Aurélie Burcelin, Rémy Lière, Philippe Krust, Andrée Chambon, Pierre Arnal, Jean-François Gourdy, Pierre Original Research 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. American Diabetes Association 2013-12 2013-11-16 /pmc/articles/PMC3837069/ /pubmed/23903353 http://dx.doi.org/10.2337/db13-0282 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Handgraaf, Sandra Riant, Elodie Fabre, Aurélie Waget, Aurélie Burcelin, Rémy Lière, Philippe Krust, Andrée Chambon, Pierre Arnal, Jean-François Gourdy, Pierre
spellingShingle	Handgraaf, Sandra Riant, Elodie Fabre, Aurélie Waget, Aurélie Burcelin, Rémy Lière, Philippe Krust, Andrée Chambon, Pierre Arnal, Jean-François Gourdy, Pierre Prevention of Obesity and Insulin Resistance by Estrogens Requires ERα Activation Function-2 (ERαAF-2), Whereas ERαAF-1 Is Dispensable
author_facet	Handgraaf, Sandra Riant, Elodie Fabre, Aurélie Waget, Aurélie Burcelin, Rémy Lière, Philippe Krust, Andrée Chambon, Pierre Arnal, Jean-François Gourdy, Pierre
author_sort	Handgraaf, Sandra
title	Prevention of Obesity and Insulin Resistance by Estrogens Requires ERα Activation Function-2 (ERαAF-2), Whereas ERαAF-1 Is Dispensable
title_short	Prevention of Obesity and Insulin Resistance by Estrogens Requires ERα Activation Function-2 (ERαAF-2), Whereas ERαAF-1 Is Dispensable
title_full	Prevention of Obesity and Insulin Resistance by Estrogens Requires ERα Activation Function-2 (ERαAF-2), Whereas ERαAF-1 Is Dispensable
title_fullStr	Prevention of Obesity and Insulin Resistance by Estrogens Requires ERα Activation Function-2 (ERαAF-2), Whereas ERαAF-1 Is Dispensable
title_full_unstemmed	Prevention of Obesity and Insulin Resistance by Estrogens Requires ERα Activation Function-2 (ERαAF-2), Whereas ERαAF-1 Is Dispensable
title_sort	prevention of obesity and insulin resistance by estrogens requires erα activation function-2 (erαaf-2), whereas erαaf-1 is dispensable
description	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.
publisher	American Diabetes Association
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837069/
_version_	1612029914771357696

Prevention of Obesity and Insulin Resistance by Estrogens Requires ERα Activation Function-2 (ERαAF-2), Whereas ERαAF-1 Is Dispensable

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