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

Abstract

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. 17a-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17a-estradiol elicits these benefits remain unresolved. Herein, we show that 17a-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor a (ERa) to that of 17b-estradiol. In addition, we show that the ablation of ERa completely attenuates the beneficial metabolic effects of 17a-E2 in male mice. Our findings suggest that 17a-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17a-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17a-E2 are not limited to mice. Collectively, these studies suggest ERa may be a drug target for mitigating chronic diseases in male mammals.