Targeting p21(Cip1) highly expressing cells in adipose tissue alleviates insulin resistance in obesity
| Autor: | 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, null Kshitiz, George A. Kuchel, Alexander Meves, Tamar Tchkonia, James L. Kirkland, Paul Robson, Ming Xu |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Physiology
Xenotransplantation medicine.medical_treatment Cell Population Adipose tissue Type 2 diabetes Diet High-Fat Article Mice Insulin resistance Diabetes mellitus medicine Animals Obesity Senolytic education Molecular Biology Cellular Senescence education.field_of_study business.industry Cell Biology medicine.disease Mice Inbred C57BL medicine.anatomical_structure Adipose Tissue Diabetes Mellitus Type 2 Cancer research Insulin Resistance business |
| Zdroj: | Cell Metab |
| Popis: | 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 plus 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. |
| Databáze: | OpenAIRE |
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