Metformin alleviates stress-induced cellular senescence of aging human adipose stromal cells and the ensuing adipocyte dysfunction

  1. Laura Le Pelletier
  2. Matthieu Mantecon
  3. Jennifer Gorwood
  4. Martine Auclair
  5. Roberta Foresti
  6. Roberto Motterlini
  7. Mireille Laforge
  8. Michael Atlan
  9. Bruno Fève
  10. Jacqueline Capeau
  11. Claire Lagathu  Is a corresponding author
  12. Veronique Bereziat  Is a corresponding author
  1. Sorbonne Université, INSERM UMR_S 938, RHU CARMMA, Institute of Cardiometabolism and Nutrition (ICAN), France
  2. University Paris-Est Créteil, INSERM, IMRB, France
  3. CNRS, INSERM UMRS_1124, Faculté des sciences fondamentales et biomédicales, Université de Paris, France
  4. Sorbonne Université, INSERM UMR_S 938, RHU CARMMA, Institute of Cardiometabolism and Nutrition (ICAN), AP-HP Tenon Hospital Department of Plastic Surgery, F-75020 Paris, France
  5. Sorbonne Université, INSERM UMR_S 938, RHU CARMMA, Institute of Cardiometabolism and Nutrition (ICAN), AP-HP, Saint Antoine Hospital, Department of Endocrinology, PRISIS, F-75012 Paris, France

Abstract

Aging is associated with central fat redistribution and insulin resistance. To identify age-related adipose features, we evaluated the senescence and adipogenic potential of adipose-derived-stromal cells (ASCs) from abdominal subcutaneous fat obtained from healthy normal-weight young (<25y) or older women (>60y). Increased cell passages of young-donor ASCs (in vitro aging), resulted in senescence but not oxidative stress. ASC-derived adipocytes presented impaired adipogenesis but no early mitochondrial dysfunction. Conversely, aged-donor ASCs at early passages displayed oxidative stress and mild senescence. ASC-derived adipocytes exhibited oxidative stress, and early mitochondrial dysfunction but adipogenesis was preserved. In vitro aging of aged-donor ASCs resulted in further increased senescence, mitochondrial dysfunction, oxidative stress and severe adipocyte dysfunction. When in vitro aged young-donor ASCs were treated with metformin, no alteration was alleviated. Conversely, metformin treatment of aged-donor ASCs decreased oxidative stress and mitochondrial dysfunction resulting in decreased senescence. Metformin's prevention of oxidative stress and of the resulting senescence improved the cells' adipogenic capacity and insulin sensitivity. This effect was mediated by the activation of AMP-activated-protein-kinase as revealed by its specific inhibition and activation. Overall, aging ASC-derived adipocytes presented impaired adipogenesis and insulin sensitivity. Targeting stress-induced senescence of ASCs with metformin may improve age-related adipose tissue dysfunction.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Laura Le Pelletier

    Metabolism and Inflammation, Sorbonne Université, INSERM UMR_S 938, RHU CARMMA, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Matthieu Mantecon

    Metabolism and Inflammation, Sorbonne Université, INSERM UMR_S 938, RHU CARMMA, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Jennifer Gorwood

    Metabolism and Inflammation, Sorbonne Université, INSERM UMR_S 938, RHU CARMMA, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Martine Auclair

    Metabolism and Inflammation, Sorbonne Université, INSERM UMR_S 938, RHU CARMMA, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Roberta Foresti

    University Paris-Est Créteil, INSERM, IMRB, Créteil, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Roberto Motterlini

    University Paris-Est Créteil, INSERM, IMRB, Créteil, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Mireille Laforge

    CNRS, INSERM UMRS_1124, Faculté des sciences fondamentales et biomédicales, Université de Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Michael Atlan

    Metabolism and Inflammation, Sorbonne Université, INSERM UMR_S 938, RHU CARMMA, Institute of Cardiometabolism and Nutrition (ICAN), AP-HP Tenon Hospital Department of Plastic Surgery, F-75020 Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Bruno Fève

    Metabolism and Inflammation, Sorbonne Université, INSERM UMR_S 938, RHU CARMMA, Institute of Cardiometabolism and Nutrition (ICAN), AP-HP, Saint Antoine Hospital, Department of Endocrinology, PRISIS, F-75012 Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Jacqueline Capeau

    Metabolism and Inflammation, Sorbonne Université, INSERM UMR_S 938, RHU CARMMA, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Claire Lagathu

    Metabolism and Inflammation, Sorbonne Université, INSERM UMR_S 938, RHU CARMMA, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
    For correspondence
    claire.lagathu@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
  12. Veronique Bereziat

    Metabolism and Inflammation, Sorbonne Université, INSERM UMR_S 938, RHU CARMMA, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
    For correspondence
    veronique.bereziat@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9795-549X

Funding

Fondation pour la Recherche Médicale (EQU201903007868)

  • Bruno Fève

Agence Nationale de la Recherche (RHU-ANR-15-RHUS-0003)

  • Jacqueline Capeau

Institut National de la Santé et de la Recherche Médicale

  • Laura Le Pelletier
  • Matthieu Mantecon
  • Jennifer Gorwood
  • Martine Auclair
  • Roberta Foresti
  • Roberto Motterlini
  • Michael Atlan
  • Bruno Fève
  • Jacqueline Capeau
  • Claire Lagathu
  • Veronique Bereziat

Sorbonne Universite

  • Laura Le Pelletier
  • Matthieu Mantecon
  • Jennifer Gorwood
  • Martine Auclair
  • Michael Atlan
  • Bruno Fève
  • Jacqueline Capeau
  • Claire Lagathu
  • Veronique Bereziat

Universite Paris Est Creteil

  • Roberta Foresti
  • Roberto Motterlini

Universite de Paris

  • Mireille Laforge

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2021, Le Pelletier 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. Laura Le Pelletier
  2. Matthieu Mantecon
  3. Jennifer Gorwood
  4. Martine Auclair
  5. Roberta Foresti
  6. Roberto Motterlini
  7. Mireille Laforge
  8. Michael Atlan
  9. Bruno Fève
  10. Jacqueline Capeau
  11. Claire Lagathu
  12. Veronique Bereziat
(2021)
Metformin alleviates stress-induced cellular senescence of aging human adipose stromal cells and the ensuing adipocyte dysfunction
eLife 10:e62635.
https://doi.org/10.7554/eLife.62635

Share this article

https://doi.org/10.7554/eLife.62635

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