Open AccessTargeting senescent cells alleviates obesity‐induced metabolic dysfunction
Author(s) -
Palmer Allyson K.,
Xu Ming,
Zhu Yi,
Pirtskhalava Tamar,
Weivoda Megan M.,
Hachfeld Christine M.,
Prata Larissa G.,
Dijk Theo H.,
Verkade Esther,
CasaclangVerzosa Grace,
Johnson Kurt O.,
Cubro Hajrunisa,
Doornebal Ewald J.,
Ogrodnik Mikolaj,
Jurk Diana,
Jensen Michael D.,
Chini Eduardo N.,
Miller Jordan D.,
Matveyenko Aleksey,
Stout Michael B.,
Schafer Marissa J.,
White Thomas A.,
Hickson LaTonya J.,
Demaria Marco,
Garovic Vesna,
Grande Joseph,
Arriaga Edgar A.,
Kuipers Folkert,
Zglinicki Thomas,
LeBrasseur Nathan K.,
Campisi Judith,
Tchkonia Tamar,
Kirkland James L.
Publication year - 2019
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12950
Subject(s) - adipose tissue , inflammation , biology , insulin resistance , adipogenesis , endocrinology , medicine , diabetes mellitus , metabolic syndrome , adipose tissue macrophages , cancer research , immunology
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.