Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity
Cell Metab 2022 Jan 4; 34(1):75-89.e8
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.
Wang, Lichao; Wang, Binsheng; Gasek, Nathan S; Zhou, Yueying; Cohn, Rachel L; Martin, Dominique E; Zuo, Wulin; Flynn, William F; Guo, Chun; Jellison, Evan R; Kim, Taewan; Prata, Larissa G P Langhi; Palmer, Allyson K; Li, Ming; Inman, Christina L; Barber, Lauren S; Al-Naggar, Iman M A; Zhou, Yanjiao; Du, Wenqiang; Kshitiz; Kuchel, George A; Meves, Alexander; Tchkonia, Tamar; Kirkland, James L; Robson, Paul; and Xu, Ming, "Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity" (2022). Faculty Research 2022. 18.