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Targeting senescent cells alleviates obesity-induced metabolic dysfunction

Lookup NU author(s): Dr Mikolaj Ogrodnik, Dr Diana Jurk, Professor Thomas von Zglinicki

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. 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 Ink4a 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.


Publication metadata

Author(s): Palmer AK, Xu M, Zhu Y, Pirtskhalava T, Weivoda MM, Hachfeld CM, Prata LG, van Dijk TH, Verkade E, Casaclang-Verzosa G, Johnson KO, Cubro H, Doornebal EJ, Ogrodnik M, Jurk D, Jensen MD, Chini EN, Miller JD, Matveyenko A, Stout MB, Schafer MJ, White TA, Hickson LJ, Demaria M, Garovic V, Grande J, Arriaga EA, Kuipers F, von Zglinicki T, LeBrasseur NK, Campisi J, Tchkonia T, Kirkland JL

Publication type: Article

Publication status: Published

Journal: Aging Cell

Year: 2019

Volume: 18

Issue: 3

Print publication date: 01/06/2019

Online publication date: 25/03/2019

Acceptance date: 03/03/2019

ISSN (print): 1474-9718

ISSN (electronic): 1474-9726

Publisher: Wiley-Blackwell

URL: https://doi.org/10.1111/acel.12950

DOI: 10.1111/acel.12950

PubMed id: 30907060


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