Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Elife. 2020 Dec 8;9:e59616. doi: 10.7554/eLife.59616.


Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.

Keywords: 17α-estradiol; aging; estrogen receptor; hypothalamus; medicine; metabolism; mouse; obesity; rat.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Estradiol / physiology*
  • Estrogen Receptor alpha / physiology*
  • Female
  • Gene Expression Regulation / physiology
  • Hypothalamus / metabolism
  • Hypothalamus / physiology
  • Insulin Resistance / physiology
  • Liver / metabolism
  • Liver / physiology
  • Longevity* / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Rats


  • Estrogen Receptor alpha
  • Estradiol

Associated data

  • GEO/GSE151039