Targeting senescent cells alleviates obesity-induced metabolic dysfunction

Allyson K. Palmer, Ming Xu, Yi Zhu, Tamar Pirtskhalava, Megan M. Weivoda, Christine M. Hachfeld, Larissa G. Prata, Theo H. van Dijk, Esther Verkade, Grace Casaclang-Verzosa, Kurt O. Johnson, Hajrunisa Cubro, Ewald J. Doornebal, Mikolaj Ogrodnik, Diana Jurk, Michael Dennis Jensen, Eduardo Nunes Chini, Jordan D Miller, Aleksey V Matveyenko, Michael B. Stout & 13 others Marissa J. Schafer, Thomas A. White, LaTonya Hickson, Marco Demaria, Vesna D Garovic, Joseph Peter Grande, Edgar A. Arriaga, Folkert Kuipers, Thomas von Zglinicki, Nathan K LeBrasseur, Judith Campisi, Tamar Tchkonia, James L Kirkland

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 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.

Original languageEnglish (US)
Article numbere12950
JournalAging Cell
Volume18
Issue number3
DOIs
StatePublished - Jun 1 2019

Fingerprint

Obesity
Adipose Tissue
Obese Mice
Insulin Resistance
p16 Genes
Inflammation
Adipogenesis
Podocytes
Intra-Abdominal Fat
Cell Aging
Suicide
Monocytes
Rodentia
Macrophages
Kidney
Glucose
Pharmaceutical Preparations
Therapeutics

Keywords

  • adipogenesis
  • aging
  • cellular senescence
  • dasatinib
  • quercetin
  • senolytics
  • type 2 diabetes

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Palmer, A. K., Xu, M., Zhu, Y., Pirtskhalava, T., Weivoda, M. M., Hachfeld, C. M., ... Kirkland, J. L. (2019). Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell, 18(3), [e12950]. https://doi.org/10.1111/acel.12950

Targeting senescent cells alleviates obesity-induced metabolic dysfunction. / Palmer, Allyson K.; Xu, Ming; Zhu, Yi; Pirtskhalava, Tamar; Weivoda, Megan M.; Hachfeld, Christine M.; Prata, Larissa G.; van Dijk, Theo H.; Verkade, Esther; Casaclang-Verzosa, Grace; Johnson, Kurt O.; Cubro, Hajrunisa; Doornebal, Ewald J.; Ogrodnik, Mikolaj; Jurk, Diana; Jensen, Michael Dennis; Chini, Eduardo Nunes; Miller, Jordan D; Matveyenko, Aleksey V; Stout, Michael B.; Schafer, Marissa J.; White, Thomas A.; Hickson, LaTonya; Demaria, Marco; Garovic, Vesna D; Grande, Joseph Peter; Arriaga, Edgar A.; Kuipers, Folkert; von Zglinicki, Thomas; LeBrasseur, Nathan K; Campisi, Judith; Tchkonia, Tamar; Kirkland, James L.

In: Aging Cell, Vol. 18, No. 3, e12950, 01.06.2019.

Research output: Contribution to journalArticle

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, AV, Stout, MB, Schafer, MJ, White, TA, Hickson, L, Demaria, M, Garovic, VD, Grande, JP, Arriaga, EA, Kuipers, F, von Zglinicki, T, LeBrasseur, NK, Campisi, J, Tchkonia, T & Kirkland, JL 2019, 'Targeting senescent cells alleviates obesity-induced metabolic dysfunction', Aging Cell, vol. 18, no. 3, e12950. https://doi.org/10.1111/acel.12950
Palmer AK, Xu M, Zhu Y, Pirtskhalava T, Weivoda MM, Hachfeld CM et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell. 2019 Jun 1;18(3). e12950. https://doi.org/10.1111/acel.12950
Palmer, Allyson K. ; Xu, Ming ; Zhu, Yi ; Pirtskhalava, Tamar ; Weivoda, Megan M. ; Hachfeld, Christine M. ; Prata, Larissa G. ; van Dijk, Theo H. ; Verkade, Esther ; Casaclang-Verzosa, Grace ; Johnson, Kurt O. ; Cubro, Hajrunisa ; Doornebal, Ewald J. ; Ogrodnik, Mikolaj ; Jurk, Diana ; Jensen, Michael Dennis ; Chini, Eduardo Nunes ; Miller, Jordan D ; Matveyenko, Aleksey V ; Stout, Michael B. ; Schafer, Marissa J. ; White, Thomas A. ; Hickson, LaTonya ; Demaria, Marco ; Garovic, Vesna D ; Grande, Joseph Peter ; Arriaga, Edgar A. ; Kuipers, Folkert ; von Zglinicki, Thomas ; LeBrasseur, Nathan K ; Campisi, Judith ; Tchkonia, Tamar ; Kirkland, James L. / Targeting senescent cells alleviates obesity-induced metabolic dysfunction. In: Aging Cell. 2019 ; Vol. 18, No. 3.
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AU - Weivoda, Megan M.

AU - Hachfeld, Christine M.

AU - Prata, Larissa G.

AU - van Dijk, Theo H.

AU - Verkade, Esther

AU - Casaclang-Verzosa, Grace

AU - Johnson, Kurt O.

AU - Cubro, Hajrunisa

AU - Doornebal, Ewald J.

AU - Ogrodnik, Mikolaj

AU - Jurk, Diana

AU - Jensen, Michael Dennis

AU - Chini, Eduardo Nunes

AU - Miller, Jordan D

AU - Matveyenko, Aleksey V

AU - Stout, Michael B.

AU - Schafer, Marissa J.

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AU - Demaria, Marco

AU - Garovic, Vesna D

AU - Grande, Joseph Peter

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N2 - 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.

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KW - dasatinib

KW - quercetin

KW - senolytics

KW - type 2 diabetes

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