Metformin alleviates stress-induced cellular senescence of aging human adipose stromal cells and the ensuing adipocyte dysfunction
- Sorbonne Université, INSERM UMR_S 938, RHU CARMMA, Institute of Cardiometabolism and Nutrition (ICAN), France
- University Paris-Est Créteil, INSERM, IMRB, France
- CNRS, INSERM UMRS_1124, Faculté des sciences fondamentales et biomédicales, Université de Paris, France
- 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
- 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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Author details
Veronique Bereziat
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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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
