Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity

Lichao Wang, Binsheng Wang, Nathan S. Gasek, Yueying Zhou, Rachel L. Cohn, Dominique E. Martin, Wulin Zuo, William F. Flynn, Chun Guo, Evan R. Jellison, Taewan Kim, Larissa G.P.Langhi Prata, Allyson K. Palmer, Ming Li, Christina L. Inman, Lauren S. Barber, Iman M.A. Al-Naggar, Yanjiao Zhou, Wenqiang Du, KshitizGeorge A. Kuchel, Alexander Meves, Tamar Tchkonia, James L. Kirkland, Paul Robson, Ming Xu

Research output: Contribution to journalArticlepeer-review

Abstract

Insulin resistance is a pathological state often associated with obesity, representing a major risk factor for type 2 diabetes. Limited mechanism-based strategies exist to alleviate insulin resistance. Here, using single-cell transcriptomics, we identify a small, critically important, but previously unexamined cell population, p21Cip1 highly expressing (p21high) cells, which accumulate in adipose tissue with obesity. By leveraging a p21-Cre mouse model, we demonstrate that intermittent clearance of p21high cells can both prevent and alleviate insulin resistance in obese mice. Exclusive inactivation of the NF-κB pathway within p21high cells, without killing them, attenuates insulin resistance. Moreover, fat transplantation experiments establish that p21high cells within fat are sufficient to cause insulin resistance in vivo. Importantly, a senolytic cocktail, dasatinib plus quercetin, eliminates p21high cells in human fat ex vivo and mitigates insulin resistance following xenotransplantation into immuno-deficient mice. Our findings lay the foundation for pursuing the targeting of p21high cells as a new therapy to alleviate insulin resistance.

Original languageEnglish (US)
Pages (from-to)75-89.e8
JournalCell Metabolism
Volume34
Issue number1
DOIs
StatePublished - Jan 4 2022

Keywords

  • Cellular senescence
  • diabetes
  • fat transplantation
  • NF-κB
  • senolytics
  • xenograft

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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