Abstract
Adipose tissue inflammation and dysfunction are associated with obesity‐related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug‐inducible “suicide” genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra‐abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity‐related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity‐related metabolic dysfunction and its complications.
Highlights
The prevalence of type 2 diabetes has quadrupled since 1980 (World Health Organization, 2016)
Senescent cells exist in relatively small numbers in any particular tissue, they have been associated with multiple diseases of aging and are emerging as useful therapeutic targets for age‐related diseases, including cardio‐ vascular disease, pulmonary fibrosis, neurodegeneration, and osteo‐ porosis (Farr et al, 2017; Musi et al, 2018; Roos et al, 2016; Schafer et al, 2017)
Our study indicates in several different models that senescent cell clearance may be an effective strategy for alleviating important ele‐ ments of obesity‐related metabolic dysfunction
Summary
The prevalence of type 2 diabetes has quadrupled since 1980 (World Health Organization, 2016). DIO INK‐ATTAC mice treated with AP20187 had fewer lipid droplets in muscle, measured by oil red O staining (Supporting Information Figure S5k), and less severe hepatic steatosis (Ogrodnik et al, 2017) These findings indicate that decreasing the burden of senescent cells may enhance insulin sensitivity in part by improving the proliferative and differentiation potential of adipocyte progeni‐ tors, contributing to healthier adipose tissue distribution and limiting ectopic lipid deposition (Gustafson et al, 2015). To test whether senes‐ cent cells can directly cause immune cell infiltration and there‐ fore whether targeting senescent cells reduces subsequent macrophage burden in adipose tissue, we injected monocytes that constitutively express luciferase intravenously into lean and obese (db/db) nonluciferase‐expressing INK‐ATTAC or wild‐type mice. Senolytics may alleviate senescence‐associ‐ ated complications of metabolic dysfunction, beyond the impact of glucose‐lowering and insulin sensitization that senolytics share with certain currently available diabetes treatments
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