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

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