Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce.

Autor: Li Q; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Hagberg CE; Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.; Cardiovascular Medicine Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden., Silva Cascales H; Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden., Lang S; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Hyvönen MT; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.; School of Pharmacy, University of Eastern Finland, Kuopio, Finland., Salehzadeh F; Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden., Chen P; Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.; Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Stockolm, Sweden., Alexandersson I; Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Terezaki E; Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden., Harms MJ; Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Kutschke M; Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden., Arifen N; Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden., Krämer N; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Aouadi M; Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.; Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Stockolm, Sweden., Knibbe C; CarMeN Laboratory, Lyon University, INRIA, INSA Lyon, Lyon, France., Boucher J; Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.; The Lundberg Laboratory for Diabetes Research, University of Gothenburg, Gothenburg, Sweden.; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden., Thorell A; Department of Clinical Science, Danderyds Hospital, Karolinska Institutet and Department of Surgery, Ersta Hospital, Karolinska Institutet, Stockholm, Sweden., Spalding KL; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. kirsty.spalding@ki.se.; Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. kirsty.spalding@ki.se.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2021 Nov; Vol. 27 (11), pp. 1941-1953. Date of Electronic Publication: 2021 Oct 04.
DOI: 10.1038/s41591-021-01501-8
Abstrakt: Obesity is considered an important factor for many chronic diseases, including diabetes, cardiovascular disease and cancer. The expansion of adipose tissue in obesity is due to an increase in both adipocyte progenitor differentiation and mature adipocyte cell size. Adipocytes, however, are thought to be unable to divide or enter the cell cycle. We demonstrate that mature human adipocytes unexpectedly display a gene and protein signature indicative of an active cell cycle program. Adipocyte cell cycle progression associates with obesity and hyperinsulinemia, with a concomitant increase in cell size, nuclear size and nuclear DNA content. Chronic hyperinsulinemia in vitro or in humans, however, is associated with subsequent cell cycle exit, leading to a premature senescent transcriptomic and secretory profile in adipocytes. Premature senescence is rapidly becoming recognized as an important mediator of stress-induced tissue dysfunction. By demonstrating that adipocytes can activate a cell cycle program, we define a mechanism whereby mature human adipocytes senesce. We further show that by targeting the adipocyte cell cycle program using metformin, it is possible to influence adipocyte senescence and obesity-associated adipose tissue inflammation.
(© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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