Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α
- OUHSC, United States
- The Jackson Laboratory, United States
- Mayo Clinic College of Medicine and Science, United States
- Mayo Clinic, United States
- Albert Einstein College of Medicine, United States
- Oklahoma Medical Research Foundation, United States
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.
Data availability
Sequencing data has been deposited in GEO under accession code GSE151039
-
Assessment of transcriptional ERa activity following exposure to 17a-E2 and 17b-E2NCBI Gene Expression Omnibus, GSE151039.
Article and author information
Author details
Funding
National Institutes of Health (R00 AG51661,R01 EY030513,T32 AG052363,P30 EY012190,P30 AG038072)
- Shivani N Mann
- Martin-Paul Agbaga
- Derek M Huffman
- Michael B Stout
Harold Hamm Diabetes Center (Pilot Research Funding)
- Shivani N Mann
- Michael B Stout
National Institutes of Health (R01 AG069742)
- Michael B Stout
National Institutes of Health (R01 AG059430)
- Willard M Freeman
Veterans Affairs Oklahoma City (I01BX003906)
- Willard M Freeman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Rochelle Buffenstein, Calico Life Sciences, LLC, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#19-063-SEAHI) of the University of Oklahoma Health Science Center.
Version history
- Received: June 3, 2020
- Accepted: December 7, 2020
- Accepted Manuscript published: December 8, 2020 (version 1)
- Version of Record published: December 16, 2020 (version 2)
Copyright
© 2020, Mann et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 6,162
- views
-
- 350
- downloads
-
- 28
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α
eLife 9:e59616.
https://doi.org/10.7554/eLife.59616
Further reading
-
- Medicine
- Neuroscience
Retinitis pigmentosa (RP) is an inherited retinal disease in which there is a loss of cone-mediated daylight vision. As there are >100 disease genes, our goal is to preserve cone vision in a disease gene-agnostic manner. Previously we showed that overexpressing TXNIP, an α-arrestin protein, prolonged cone vision in RP mouse models, using an AAV to express it only in cones. Here, we expressed different alleles of Txnip in the retinal pigmented epithelium (RPE), a support layer for cones. Our goal was to learn more of TXNIP’s structure-function relationships for cone survival, as well as determine the optimal cell type expression pattern for cone survival. The C-terminal half of TXNIP was found to be sufficient to remove GLUT1 from the cell surface, and improved RP cone survival, when expressed in the RPE, but not in cones. Knock-down of HSP90AB1, a TXNIP-interactor which regulates metabolism, improved the survival of cones alone and was additive for cone survival when combined with TXNIP. From these and other results, it is likely that TXNIP interacts with several proteins in the RPE to indirectly support cone survival, with some of these interactions different from those that lead to cone survival when expressed only in cones.
-
- Medicine
Caesarean section scar diverticulum (CSD) is a significant cause of infertility among women who have previously had a Caesarean section, primarily due to persistent inflammatory exudation associated with this condition. Even though abnormal bacterial composition is identified as a critical factor leading to this chronic inflammation, clinical data suggest that a long-term cure is often unattainable with antibiotic treatment alone. In our study, we employed metagenomic analysis and mass spectrometry techniques to investigate the fungal composition in CSD and its interaction with bacteria. We discovered that local fungal abnormalities in CSD can disrupt the stability of the bacterial population and the entire microbial community by altering bacterial abundance via specific metabolites. For instance, Lachnellula suecica reduces the abundance of several Lactobacillus spp., such as Lactobacillus jensenii, by diminishing the production of metabolites like Goyaglycoside A and Janthitrem E. Concurrently, Clavispora lusitaniae and Ophiocordyceps australis can synergistically impact the abundance of Lactobacillus spp. by modulating metabolite abundance. Our findings underscore that abnormal fungal composition and activity are key drivers of local bacterial dysbiosis in CSD.
