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 D. Jensen, Eduardo N. Chini, Jordan D. Miller, Aleksey Matveyenko, Michael B. StoutMarissa J. Schafer, Thomas A. White, La Tonya J. Hickson, Marco Demaria, Vesna Garovic, Joseph Grande, Edgar A. Arriaga, Folkert Kuipers, Thomas von Zglinicki, Nathan K. LeBrasseur, Judith Campisi, Tamar Tchkonia, James L. Kirkland

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

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.

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

Bibliographical note

Funding Information:
The authors are grateful to J. Armstrong for administrative assistance, K. Mantz for pancreatic histology analysis, M. Mahlman for obtaining human adipose samples, and C. Inman for assistance with animal husbandry. This work was supported by NIH grants AG13925 (J.L.K.), AG041122 (J.L.K.), AG31736 (Project 4: J.L.K.), AG044396 (J.L.K.), DK50456 (J.L.K., M.D.J.), AG46061 (A.K.P.), AG51661 (M.B.S), Minnesota Partnership for Biotechnology grant MNP IF #14.06 (J.L.K., E.A.), Robert and Arlene Kogod, the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), the Glenn (J.L.K., N.K.L.), Ted Nash Long Life (J.L.K.), and Noaber Foundations (J.L.K.), and BBSRC grants BB/K019260/1 and BB/M023389/1 (M.O., T.vZ.). Insulin and F4/80 immunohistochemistry was performed by the Ohio State University Comparative Pathology & Mouse Phenotyping Shared Resource (CPMPSR), supported in part by NCI grant P30 CA016058. M.X. received the support of the Regenerative Medicine Initiative for Diabetes-Career Development Award, the Glenn/AFAR Postdoctoral Fellowship for Translational Research on Aging, and an Irene Diamond Fund/AFAR Postdoctoral Transition Award in Aging. E.D. was supported by a stipend from Noaber Foundation. A.K.P. received a Glenn/AFAR Scholarship for Research in the Biology of Aging. A.K.P. thanks the Mayo Clinic Medical Scientist Training Program for fostering an outstanding environment for physician–scientist training.

Funding Information:
The authors are grateful to J. Armstrong for administrative as‐ sistance, K. Mantz for pancreatic histology analysis, M. Mahlman for obtaining human adipose samples, and C. Inman for assistance with animal husbandry. This work was supported by NIH grants AG13925 (J.L.K.), AG041122 (J.L.K.), AG31736 (Project 4: J.L.K.), AG044396 (J.L.K.), DK50456 (J.L.K., M.D.J.), AG46061 (A.K.P.), AG51661 (M.B.S), Minnesota Partnership for Biotechnology grant MNP IF #14.06 (J.L.K., E.A.), Robert and Arlene Kogod, the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), the Glenn (J.L.K., N.K.L.), Ted Nash Long Life (J.L.K.), and Noaber Foundations (J.L.K.), and BBSRC grants BB/K019260/1 and BB/ M023389/1 (M.O., T.vZ.). Insulin and F4/80 immunohistochem‐ istry was performed by the Ohio State University Comparative Pathology & Mouse Phenotyping Shared Resource (CPMPSR), sup‐ ported in part by NCI grant P30 CA016058. M.X. received the sup‐ port of the Regenerative Medicine Initiative for Diabetes‐Career Development Award, the Glenn/AFAR Postdoctoral Fellowship for Translational Research on Aging, and an Irene Diamond Fund/ AFAR Postdoctoral Transition Award in Aging. E.D. was supported by a stipend from Noaber Foundation. A.K.P. received a Glenn/ AFAR Scholarship for Research in the Biology of Aging. A.K.P. thanks the Mayo Clinic Medical Scientist Training Program for fos‐ tering an outstanding environment for physician–scientist training.

Publisher Copyright:
© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Keywords

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

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