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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.

SUBMITTER: Palmer AK 

PROVIDER: S-EPMC6516193 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Targeting senescent cells alleviates obesity-induced metabolic dysfunction.

Palmer Allyson K AK   Xu Ming M   Zhu Yi Y   Pirtskhalava Tamar T   Weivoda Megan M MM   Hachfeld Christine M CM   Prata Larissa G LG   van Dijk Theo H TH   Verkade Esther E   Casaclang-Verzosa Grace G   Johnson Kurt O KO   Cubro Hajrunisa H   Doornebal Ewald J EJ   Ogrodnik Mikolaj M   Jurk Diana D   Jensen Michael D MD   Chini Eduardo N EN   Miller Jordan D JD   Matveyenko Aleksey A   Stout Michael B MB   Schafer Marissa J MJ   White Thomas A TA   Hickson LaTonya J LJ   Demaria Marco M   Garovic Vesna V   Grande Joseph J   Arriaga Edgar A EA   Kuipers Folkert F   von Zglinicki Thomas T   LeBrasseur Nathan K NK   Campisi Judith J   Tchkonia Tamar T   Kirkland James L JL  

Aging cell 20190325 3


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<sup>Ink4a</s  ...[more]

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