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Am J Pathol. 2017 Jun;187(6):1273-1287. doi: 10.1016/j.ajpath.2017.02.013. Epub 2017 May 11.

Selective Activation of Estrogen Receptor α Activation Function-1 Is Sufficient to Prevent Obesity, Steatosis, and Insulin Resistance in Mouse.

Author information

1
Institute of Metabolic and Cardiovascular Diseases (I2MC), UMR1048, INSERM, UPS, Université de Toulouse, Toulouse, France.
2
STROMALab, CNRS ERL5311, EFS, ENVT, INSERM U1031, UPS, Université de Toulouse, Toulouse, France.
3
Institute of Metabolic and Cardiovascular Diseases (I2MC), UMR1048, INSERM, UPS, Université de Toulouse, Toulouse, France; INRA UMR1331, ToxAlim, Université de Toulouse III, Toulouse, France.
4
INRA UMR1331, ToxAlim, Université de Toulouse III, Toulouse, France.
5
Institute of Metabolic and Cardiovascular Diseases (I2MC), UMR1048, INSERM, UPS, Université de Toulouse, Toulouse, France; Service de Diabétologie, CHU de Toulouse, Toulouse, France. Electronic address: pierre.gourdy@inserm.fr.

Abstract

Estrogen receptor α (ERα) regulates gene transcription through two activation functions (ERα-AF1 and ERα-AF2). We recently found that the protection conferred by 17β-estradiol against obesity and insulin resistance requires ERα-AF2 but not ERα-AF1. However, the interplay between the two ERα-AFs is poorly understood in vivo and the metabolic influence of a specific ERα-AF1 action remains to be explored. To this end, wild-type, ERα-deficient, or ERα-AF1-deficient ovariectomized female mice were fed a high-fat diet and concomitantly administered with vehicle or tamoxifen, a selective ER modulator that acts as a ERα-AF1 agonist/ERα-AF2 antagonist. In ovariectomized wild-type mice, tamoxifen significantly reduced food intake and totally prevented adiposity, insulin resistance, and steatosis. These effects were abolished in ERα-deficient and ERα-AF1-deficient mice, revealing the specific role of ERα-AF1 activation. Finally, hepatic gene expression changes elicited by tamoxifen in wild-type mice were abrogated in ERα-AF1-deficient mice. The combination of pharmacologic and transgenic approaches thus indicates that selective ERα-AF1 activation by tamoxifen is sufficient to elicit metabolic protection, contrasting with the specific requirement of ERα-AF2 in the metabolic actions of 17β-estradiol. This redundancy in the ability of the two ERα-AFs to separately mediate metabolic prevention strikingly contrasts with the contribution of both ERα-AFs in breast cancer proliferation, shedding new light on the therapeutic potential of selective ER modulation.

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