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Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity
Lichao Wang1, Binsheng Wang1, Nathan S Gasek1
1UConn Center on Aging, UConn Health, Farmington, CT 06030, USA; Department of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030, USA.
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.
Insights
Obesity-linked insulin resistance can be treated by targeting a newly discovered cell population, p21-high cells. Eliminating these cells, or inhibiting their NF-κB pathway, improves insulin sensitivity in mice and human fat tissue.
Area of Science:
- Metabolic disease research
- Cell biology
- Immunology
Background:
- Insulin resistance, a precursor to type 2 diabetes, is strongly linked to obesity.
- Current therapeutic strategies for insulin resistance are limited in scope and mechanism.
- A specific cell population contributing to insulin resistance has not been well-defined.
Purpose of the Study:
- To identify novel cellular mechanisms underlying obesity-induced insulin resistance.
- To investigate the role of p21-high cells in the development of insulin resistance.
- To explore therapeutic strategies targeting p21-high cells for insulin resistance.
Main Methods:
- Single-cell transcriptomics to identify p21-high cells in adipose tissue.
- Utilizing a p21-Cre mouse model for targeted cell clearance and pathway manipulation.
- Fat transplantation and xenotransplantation models to assess in vivo effects.
- Employing a senolytic cocktail (dasatinib plus quercetin) to eliminate p21-high cells.
Main Results:
- Obesity leads to the accumulation of p21-high cells in adipose tissue.
- Intermittent clearance of p21-high cells prevents and reverses insulin resistance in obese mice.
- Inactivating the NF-κB pathway in p21-high cells attenuates insulin resistance.
- p21-high cells are sufficient to induce insulin resistance, as shown by fat transplantation.
- Dasatinib plus quercetin eliminates p21-high cells in human fat and mitigates insulin resistance in xenotransplantation models.
Conclusions:
- p21-high cells represent a critical, previously unrecognized cell population driving insulin resistance in obesity.
- Targeting p21-high cells, via clearance or pathway inhibition, offers a promising therapeutic avenue for insulin resistance.
- Senolytic therapy targeting p21-high cells demonstrates potential for treating human insulin resistance.
