UConn Center on Aging, UConn Health, Farmington, CT 06030, USA; Department of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030, USA.
Xiangya Stomatological Hospital, Central South University, Changsha, 86-410000, China; Center for Regenerative Medicine and Skeletal Development, UConn Health, Farmington, CT 06030, USA.
Cell Metab. 2022 Jan 4;34(1):75-89.e8. doi: 10.1016/j.cmet.2021.11.002. Epub 2021 Nov 22.
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 highly expressing (p21) cells, which accumulate in adipose tissue with obesity. By leveraging a p21-Cre mouse model, we demonstrate that intermittent clearance of p21 cells can both prevent and alleviate insulin resistance in obese mice. Exclusive inactivation of the NF-κB pathway within p21 cells, without killing them, attenuates insulin resistance. Moreover, fat transplantation experiments establish that p21 cells within fat are sufficient to cause insulin resistance in vivo. Importantly, a senolytic cocktail, dasatinib plus quercetin, eliminates p21 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 cells as a new therapy to alleviate insulin resistance.
胰岛素抵抗是一种与肥胖症相关的病理状态，是 2 型糖尿病的主要危险因素。目前存在的基于机制的治疗策略有限，无法缓解胰岛素抵抗。在这里，我们使用单细胞转录组学技术，鉴定出一个小而重要但以前未被研究的细胞群体，即 p21 高表达（p21）细胞，其在肥胖症患者的脂肪组织中积累。通过利用 p21-Cre 小鼠模型，我们证明间歇性清除 p21 细胞可预防和缓解肥胖小鼠的胰岛素抵抗。特异性抑制 p21 细胞中的 NF-κB 通路（不杀死它们）可减轻胰岛素抵抗。此外，脂肪移植实验表明，脂肪内的 p21 细胞足以在体内引起胰岛素抵抗。重要的是，一种 senolytic 鸡尾酒（达沙替尼加槲皮素）可消除体外人脂肪中的 p21 细胞，并减轻异种移植到免疫缺陷小鼠后的胰岛素抵抗。我们的研究结果为靶向 p21 细胞作为一种新的治疗方法来缓解胰岛素抵抗奠定了基础。
