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Targeting senescent cells alleviates obesity-induced metabolic dysfunction.
- Source :
-
Aging cell [Aging Cell] 2019 Jun; Vol. 18 (3), pp. e12950. Date of Electronic Publication: 2019 Mar 25. - Publication Year :
- 2019
-
Abstract
- Adipose tissue inflammation and dysfunction are associated with obesity-related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug-inducible "suicide" genes driven by the p16 <superscript>Ink4a</superscript> promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra-abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity-related metabolic dysfunction and its complications.<br /> (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
- Subjects :
- Adipocytes cytology
Adipocytes drug effects
Adipogenesis physiology
Adipose Tissue drug effects
Aging metabolism
Aging pathology
Animals
Cell Death drug effects
Cell Death genetics
Cell Death physiology
Cell Line
Cellular Senescence genetics
Cellular Senescence physiology
Cyclin-Dependent Kinase Inhibitor p16 metabolism
Dasatinib pharmacology
Female
Ganciclovir pharmacology
Glucose metabolism
Humans
Macrophages drug effects
Macrophages metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Quercetin pharmacology
Adipocytes metabolism
Adipogenesis drug effects
Adipose Tissue metabolism
Cellular Senescence drug effects
Inflammation metabolism
Insulin Resistance physiology
Obesity metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1474-9726
- Volume :
- 18
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Aging cell
- Publication Type :
- Academic Journal
- Accession number :
- 30907060
- Full Text :
- https://doi.org/10.1111/acel.12950