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 language | English (US) |
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Pages (from-to) | 75-89.e8 |
Journal | Cell Metabolism |
Volume | 34 |
Issue number | 1 |
DOIs | |
State | Published - Jan 4 2022 |
Keywords
- Cellular senescence
- NF-κB
- diabetes
- fat transplantation
- senolytics
- xenograft
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology