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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
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.
Reviewing Editor
- Jessica K Tyler, Weill Cornell Medicine, United States
Version history
- Received: September 1, 2020
- Preprint posted: October 6, 2020 (view preprint)
- Accepted: September 3, 2021
- Accepted Manuscript published: September 21, 2021 (version 1)
- Version of Record published: October 19, 2021 (version 2)
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.
Metrics
-
- 3,248
- views
-
- 573
- downloads
-
- 40
- 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)
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
Further reading
-
- Cell Biology
- Neuroscience
The cytosolic proteins synucleins and synapsins are thought to play cooperative roles in regulating synaptic vesicle (SV) recycling, but mechanistic insight is lacking. Here, we identify the synapsin E-domain as an essential functional binding-partner of α-synuclein (α-syn). Synapsin E-domain allows α-syn functionality, binds to α-syn, and is necessary and sufficient for enabling effects of α-syn at synapses of cultured mouse hippocampal neurons. Together with previous studies implicating the E-domain in clustering SVs, our experiments advocate a cooperative role for these two proteins in maintaining physiologic SV clusters.
-
- Cell Biology
Here, we investigated the mechanisms by which aging-related reductions of the levels of Numb in skeletal muscle fibers contribute to loss of muscle strength and power, two critical features of sarcopenia. Numb is an adaptor protein best known for its critical roles in development, including asymmetric cell division, cell-type specification, and termination of intracellular signaling. Numb expression is reduced in old humans and mice. We previously showed that, in mouse skeletal muscle fibers, Numb is localized to sarcomeres where it is concentrated near triads; conditional inactivation of Numb and a closely related protein Numb-like (Numbl) in mouse myofibers caused weakness, disorganization of sarcomeres, and smaller mitochondria with impaired function. Here, we found that a single knockout of Numb in myofibers causes reduction in tetanic force comparable to a double Numb, Numbl knockout. We found by proteomics analysis of protein complexes isolated from C2C12 myotubes by immunoprecipitation using antibodies against Numb that Septin 7 is a potential Numb-binding partner. Septin 7 is a member of the family of GTP-binding proteins that organize into filaments, sheets, and rings, and is considered part of the cytoskeleton. Immunofluorescence evaluation revealed a partial overlap of staining for Numb and Septin 7 in myofibers. Conditional, inducible knockouts of Numb led to disorganization of Septin 7 staining in myofibers. These findings indicate that Septin 7 is a Numb-binding partner and suggest that interactions between Numb and Septin 7 are critical for structural organization of the sarcomere and muscle contractile function.
