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Title: 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 p 16Ink4a 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.

Authors:
 [1];  [2];  [1];  [1];  [1];  [1];  [1];  [3];  [3];  [1];  [1];  [1];  [1];  [4];  [4];  [1];  [1];  [1];  [1];  [5] more »;  [1];  [1];  [1];  [6];  [1];  [1];  [7];  [3];  [8];  [1];  [9];  [1];  [1] « less
  1. Mayo Clinic, Rochester, MN (United States)
  2. Mayo Clinic, Rochester, MN (United States); Univ. of Connecticut Health, Farmington, CT (United States)
  3. Univ. of Groningen, Groningen (The Netherlands)
  4. Mayo Clinic, Rochester, MN (United States); Newcastle Univ., Newcastle upon Tyne (United Kingdom)
  5. Mayo Clinic, Rochester, MN (United States); Univ. of Oklahoma Health Sciences Center, Oklahoma City, OK (United States)
  6. Buck Inst. for Research on Aging, Novato, CA (United States); Univ. of Groningen, Groningen (The Netherlands)
  7. Univ. of Minnesota, Minneapolis, MN (United States)
  8. Newcastle Univ., Newcastle upon Tyne (United Kingdom)
  9. Buck Inst. for Research on Aging, Novato, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1560598
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Aging Cell
Additional Journal Information:
Journal Volume: 18; Journal Issue: 3; Journal ID: ISSN 1474-9718
Publisher:
Anatomical Society - Wiley
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; adipogenesis; aging; cellular senescence; dasatinib; quercetin; senolytics; type 2 diabetes

Citation Formats

Palmer, Allyson K., Xu, Ming, Zhu, Yi, Pirtskhalava, Tamar, Weivoda, Megan M., Hachfeld, Christine M., Prata, Larissa G., Dijk, Theo H., Verkade, Esther, Casaclang‐Verzosa, 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 von, LeBrasseur, Nathan K., Campisi, Judith, Tchkonia, Tamar, and Kirkland, James L. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. United States: N. p., 2019. Web. doi:10.1111/acel.12950.
Palmer, Allyson K., Xu, Ming, Zhu, Yi, Pirtskhalava, Tamar, Weivoda, Megan M., Hachfeld, Christine M., Prata, Larissa G., Dijk, Theo H., Verkade, Esther, Casaclang‐Verzosa, 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 von, LeBrasseur, Nathan K., Campisi, Judith, Tchkonia, Tamar, & Kirkland, James L. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. United States. doi:10.1111/acel.12950.
Palmer, Allyson K., Xu, Ming, Zhu, Yi, Pirtskhalava, Tamar, Weivoda, Megan M., Hachfeld, Christine M., Prata, Larissa G., Dijk, Theo H., Verkade, Esther, Casaclang‐Verzosa, 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 von, LeBrasseur, Nathan K., Campisi, Judith, Tchkonia, Tamar, and Kirkland, James L. Mon . "Targeting senescent cells alleviates obesity-induced metabolic dysfunction". United States. doi:10.1111/acel.12950. https://www.osti.gov/servlets/purl/1560598.
@article{osti_1560598,
title = {Targeting senescent cells alleviates obesity-induced metabolic dysfunction},
author = {Palmer, Allyson K. and Xu, Ming and Zhu, Yi and Pirtskhalava, Tamar and Weivoda, Megan M. and Hachfeld, Christine M. and Prata, Larissa G. and Dijk, Theo H. and Verkade, Esther and Casaclang‐Verzosa, Grace and Johnson, Kurt O. and Cubro, Hajrunisa and Doornebal, Ewald J. and Ogrodnik, Mikolaj and Jurk, Diana and Jensen, Michael D. and Chini, Eduardo N. and Miller, Jordan D. and Matveyenko, Aleksey and Stout, Michael B. and Schafer, Marissa J. and White, Thomas A. and Hickson, LaTonya J. and Demaria, Marco and Garovic, Vesna and Grande, Joseph and Arriaga, Edgar A. and Kuipers, Folkert and Zglinicki, Thomas von and LeBrasseur, Nathan K. and Campisi, Judith and Tchkonia, Tamar and Kirkland, James L.},
abstractNote = {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.},
doi = {10.1111/acel.12950},
journal = {Aging Cell},
number = 3,
volume = 18,
place = {United States},
year = {2019},
month = {3}
}

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