1. Medicine
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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
Research Article
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Cite this article as: eLife 2020;9:e59616 doi: 10.7554/eLife.59616

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.

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.

Reviewing Editor

  1. Rochelle Buffenstein, Calico Life Sciences, LLC, United States

Publication 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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Further reading

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    The CX3CR1 (chemokine (C-X3-C motif) receptor 1) expression levels on immune cells have significant importance in maintaining tissue homeostasis under physiological and pathological conditions. The factors implicated in the regulation of CX3CR1 and its specific ligand CX3CL1 (fractalkine) expression remain largely unknown. Recent studies provide evidence that host`s misfolded proteins occurring in the forms of polymers or amyloid fibrils can regulate CX3CR1 expression. Herein, a novel example demonstrates that polymers of human ZZ alpha-1 antitrypsin (Z-AAT) protein, resulting from its conformational misfolding due to the Z (Glu342Lys) mutation in SERPINA1 gene, strongly lower CX3CR1 mRNA expression in human PBMCs. This parallels with increase of intracellular levels of CX3CR1 and Z-AAT proteins. Presented data indicate the involvement of the CX3CR1 pathway in the Z-AAT-related disorders and further support the role of misfolded proteins in CX3CR1 regulation.

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    Melanie Castro-Mollo et al.
    Research Article

    Background: Erythroblast erythroferrone (ERFE) secretion inhibits hepcidin expression by sequestering several bone morphogenetic protein (BMP) family members to increase iron availability for erythropoiesis.

    Methods: To address whether ERFE functions also in bone and whether the mechanism of ERFE action in bone involves BMPs, we utilize the Erfe-/- mouse model as well as β–thalassemic (Hbbth3/+) mice with systemic loss of ERFE expression. In additional, we employ comprehensive skeletal phenotyping analyses as well as functional assays in vitro to address mechanistically the function of ERFE in bone.

    Results: We report that ERFE expression in osteoblasts is higher compared with erythroblasts, is independent of erythropoietin, and functional in suppressing hepatocyte hepcidin expression. Erfe-/- mice display low–bone–mass arising from increased bone resorption despite a concomitant increase in bone formation. Consistently, Erfe-/- osteoblasts exhibit enhanced mineralization, Sost and Rankl expression, and BMP–mediated signaling ex vivo. The ERFE effect on osteoclasts is mediated through increased osteoblastic RANKL and sclerostin expression, increasing osteoclastogenesis in Erfe-/- mice. Importantly, Erfe loss in Hbbth3/+ mice, a disease model with increased ERFE expression, triggers profound osteoclastic bone resorption and bone loss.

    Conclusions: Together, ERFE exerts an osteoprotective effect by modulating BMP signaling in osteoblasts, decreasing RANKL production to limit osteoclastogenesis, and prevents excessive bone loss during expanded erythropoiesis in β–thalassemia.

    Funding: Y.Z.G. acknowledges the support of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK107670 to Y.Z.G. and DK095112 to R.F., S.R., and Y.Z.G.). M.Z. acknowledges the support of the National Institute on Aging (U19 AG60917) and NIDDK (R01 DK113627). T.Y. acknowledges the support of the National Institute on Aging (R01 AG71870). S.R. acknowledges the support of NIDDK (R01 DK090554) and Commonwealth Universal Research Enhancement (C.U.R.E.) Program Pennsylvania.