Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity

Document Type

Article

Publication Date

1-4-2022

Publication Title

Cell Metab

Keywords

JGM

JAX Source

Cell Metab 2022 Jan 4; 34(1):75-89.e8

Volume

34

Issue

1

First Page

75

Last Page

89

ISSN

1932-7420

PMID

34813734

DOI

https://doi.org/10.1016/j.cmet.2021.11.002

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.

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