“Targeting p21^Cip1 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, George A. Kuchel, Alexander Meves, Tamar Tchkonia, James L. Kirkland, Paul Robson, Ming Xu2021-11-22 (D+Q senolytic; similar)⁠:

• p21^high cells, distinct from p16^high cells, accumulate in fat with obesity

• Intermittent p21^high cell clearance both prevents and alleviates insulin resistance

• Exclusive inactivation of NF-κB in p21^high cells improves insulin sensitivity

• A senolytic reduces p21^high cells in human fat and alleviates its metabolic harm in vivo

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, p21^Cip1 highly expressing (p21^high) cells, which accumulate in adipose tissue with obesity.

By leveraging a p21-Cre mouse model, we demonstrate that intermittent clearance of p21^high cells can both prevent and alleviate insulin resistance in obese mice. Exclusive inactivation of the NF-κB pathway within p21^high cells, without killing them, attenuates insulin resistance. Moreover, fat transplantation experiments establish that p21^high cells within fat are sufficient to cause insulin resistance in vivo. Importantly, a senolytic cocktail, dasatinib+quercetin, eliminates p21^high 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 p21^high cells as a new therapy to alleviate insulin resistance.

[Keywords: Cellular senescence, diabetes, senolytics, fat transplantation, NF-κB, xenograft]

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