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

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


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.

MeSH terms

  • Animals
  • Diet, High-Fat
  • Drug Evaluation, Preclinical / methods
  • Estrogen Receptor alpha / antagonists & inhibitors
  • Estrogen Receptor alpha / deficiency
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / physiology*
  • Fatty Liver / etiology
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Fatty Liver / prevention & control*
  • Female
  • Gene Expression Regulation / drug effects
  • Insulin Resistance / physiology*
  • Liver / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / etiology
  • Obesity / metabolism
  • Obesity / prevention & control*
  • Ovariectomy
  • Selective Estrogen Receptor Modulators / pharmacology
  • Selective Estrogen Receptor Modulators / therapeutic use*
  • Tamoxifen / pharmacology
  • Tamoxifen / therapeutic use
  • Weight Gain / drug effects


  • Estrogen Receptor alpha
  • Selective Estrogen Receptor Modulators
  • Tamoxifen