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. 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.

17α-Estradiol prevents ovariectomy-mediated obesity and bone loss

“…Interestingly, both SHAM and OVX mice receiving 17α-E2 displayed similar body mass and adiposity levels as the SHAM CON group, thereby suggesting that 17α-E2 treatment elicits similar effects as endogenous estrogens (likely 17β-E2), yet is not particularly synergistic. This suggests 17α-E2 and 17β-E2 are likely competing for the same receptors in vivo, which we provide evidence for in other reports ( Mann et al, 2020 ). We also evaluated intra- (periovarian [POV]) and extra-peritoneal (inguinal [ING]) white adipose tissue (WAT) masses because a redistribution of lipid to ectopic sites occurs and intra-peritoneal WAT depots increase with aging ( Stout et al, 2014 ; Stout et al, 2017b ).…”

“…17α-E2 has recently been shown to induce considerable benefits on healthspan and lifespan in male mice ( Harrison et al, 2014 ; Strong et al, 2016 ; Stout et al, 2017a ; Garratt et al, 2017 ; Mann et al, 2020 ; Garratt et al, 2018 ), although little benefit has been observed in females receiving the compound ( Garratt et al, 2017 ; Garratt et al, 2018 ). We have postulated that the lack of beneficial effects of 17α-E2 in females may be due to the high levels of endogenous 17β-E2, which may outcompete the less-potent 17α-E2 at estrogen receptors ( Mann et al, 2020 ). In this report we sought to determine if 17α-E2 could elicit beneficial outcomes on age-related phenotypes associated with ovariectomy in female mice, with a specific emphasis on bone loss.…”

“…Given that it elicits such robust sexually dimorphic responses in mice, studies employing 17α-E2 can provide critical insight into the mechanisms underlying the differences in aging biology between the sexes. To our knowledge, the effects of 17α-E2 on bone dynamics has not been previously evaluated, although our recent work shows that 17α-E2 induces metabolic benefits through ERα ( Mann et al, 2020 ), a receptor known to be highly involved in bone homeostasis ( Khosla and Monroe, 2018 ). This led us to hypothesize that 17α-E2 would induce beneficial effects in OVX mice, which is a model for post-menopausal bone loss in humans.…”

“…Despite the collective evidence outlined above, it must be noted that most of the studies to date have evaluated health parameters that deteriorate to a greater degree in male mammals with advancing age ( Garratt and Stout, 2018 ), including nutrient-sensing pathway perturbations, systemic metabolic parameters, and pro-inflammatory stress ( Stout et al, 2017a ; Steyn et al, 2018 ; Garratt et al, 2017 ; Mann et al, 2020 ; Garratt et al, 2018 ). In fact, it is well-established that female mammals possess an inherent advantage as compared to their male counterparts with regard to metabolic plasticity, immunological responses, and DNA damage ( Austad and Fischer, 2016 ; Moran et al, 2013 ).…”

“…This is known to be at least partially mediated by endogenous 17β-E2 due to its ability to beneficially effect a myriad of pathways and processes including glucose homeostasis, insulin sensitivity, immune cell migration and activation, and the mTOR signaling pathway in an estrogen receptor α (ERα)-dependent manner ( Mauvais-Jarvis et al, 2013 ; Bian et al, 2019 ). Despite 17α-E2 having lesser binding affinity for ERα than 17β-E2 ( Edwards and McGuire, 1980 ; Anstead et al, 1997 ), we have recently determined that ERα likely plays an important role in mediating 17α-E2 effects on health parameters in male mice ( Mann et al, 2020 ). In light of these recent findings, coupled with the fact that no studies to date have explored the effects of 17α-E2 on female-dominant age-related conditions (e.g.…”