Selective activation of estrogen receptor alpha activation function-1 is sufficient to prevent obesity, steatosis, and insulin resistance in mouse
Résumé
Estrogen receptor alpha (ER alpha) regulates gene transcription through two activation functions (ER alpha-AF1 and ER alpha-AF2). We recently found that the protection conferred by 17 beta-estradiol against obesity and insulin resistance requires ER alpha-AF2 but not ER alpha-AF1. However, the interplay between the two ER alpha-AFs is poorly understood in vivo and the metabolic influence of a specific ER alpha-AF1 action remains to be explored. To this end, wild-type, ER alpha-deficient, or ER alpha-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 ER alpha-AF1 agonist/ER alpha-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 ER alpha-deficient and ER alpha-AF1 deficient mice, revealing the specific role of ER alpha-AF1 activation. Finally, hepatic gene expression changes elicited by tamoxifen in wild-type mice were abrogated in ER alpha-AF1 deficient mice. The combination of pharmacologic and transgenic approaches thus indicates that selective ER alpha-AF1 activation by tamoxifen is sufficient to elicit metabolic protection, contrasting with the specific requirement of ER alpha-AF2 in the metabolic actions of 17 beta-estradiol. This redundancy in the ability of the two ER alpha-AFs to separately mediate metabolic prevention strikingly contrasts with the contribution of both ER alpha-AFs in breast cancer proliferation, shedding new light on the therapeutic potential of selective ER modulation.