Targeting senescent cells alleviates obesity-induced metabolic dysfunction.

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 p16Ink4a 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.

journal_name

Aging Cell

journal_title

Aging cell

authors

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,Sc

doi

10.1111/acel.12950

subject

Has Abstract

pub_date

2019-06-01 00:00:00

pages

e12950

issue

3

eissn

1474-9718

issn

1474-9726

journal_volume

18

pub_type

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