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

  1. Shivani N Mann
  2. Niran Hadad
  3. Molly Nelson Holte
  4. Alicia R Rothman
  5. Roshini Sathiaseelan
  6. Samim Ali Mondal
  7. Martin-Paul Agbaga
  8. Archana Unnikrishnan
  9. Malayannan Subramaniam
  10. John Hawse
  11. Derek M Huffman
  12. Willard M Freeman
  13. Michael B Stout  Is a corresponding author
  1. OUHSC, United States
  2. The Jackson Laboratory, United States
  3. Mayo Clinic College of Medicine and Science, United States
  4. Mayo Clinic, United States
  5. Albert Einstein College of Medicine, United States
  6. 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

The following data sets were generated

Article and author information

Author details

  1. Shivani N Mann

    Nutritional Sciences, OUHSC, Oklahoma City, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Niran Hadad

    Genomics, The Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Molly Nelson Holte

    Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Alicia R Rothman

    Nutritional Sciences, OUHSC, Oklahoma City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Roshini Sathiaseelan

    Nutritional Sciences, OUHSC, Oklahoma City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Samim Ali Mondal

    Nutritional Sciences, OUHSC, Oklahoma City, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Martin-Paul Agbaga

    Cell Biology, OUHSC, Oklahoma City, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Archana Unnikrishnan

    Biochemistry, OUHSC, Oklahoma City, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Malayannan Subramaniam

    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. John Hawse

    Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Derek M Huffman

    Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Willard M Freeman

    Genes & Human Disease, Oklahoma Medical Research Foundation, Oklahoma City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7027-999X
  13. Michael B Stout

    Nutritional Sciences, OUHSC, Oklahoma City, United States
    For correspondence
    michael-stout@ouhsc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9996-9123

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

  1. 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

  1. Received: June 3, 2020
  2. Accepted: December 7, 2020
  3. Accepted Manuscript published: December 8, 2020 (version 1)
  4. 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.

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  1. Shivani N Mann
  2. Niran Hadad
  3. Molly Nelson Holte
  4. Alicia R Rothman
  5. Roshini Sathiaseelan
  6. Samim Ali Mondal
  7. Martin-Paul Agbaga
  8. Archana Unnikrishnan
  9. Malayannan Subramaniam
  10. John Hawse
  11. Derek M Huffman
  12. Willard M Freeman
  13. Michael B Stout
(2020)
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

Share this article

https://doi.org/10.7554/eLife.59616

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