OP-27 - Cellular Senescence: At the Nexus of Mechanisms of Age- and Obesity-Related Metabolic Dysfunction

Abstract

Obesity is a leading risk factor for diabetes and its co-morbidities. Adipose dysfunction occurs in obesity-related diabetes, but mechanisms responsible have been unclear. Although senescent cells accumulate in adipose tissue in obese humans and rodents, a causal role for senescent cells remains to be proven. Cellular senescence results in replicative arrest, resistance to apoptosis, and a pro-inflammatory senescence-associated secretory phenotype (SASP). We found that inhibiting the SASP or reducing senescent cell burden alleviates metabolic and adipose tissue dysfunction in obese mice. We reduced senescent cell abundance either by intermittent activation of drug-inducible “suicide” genes driven by the p16Ink4a promoter in transgenic mice or by treatment with senolytic drugs – drugs that selectively induce apoptosis in senescent cells. Reducing senescent cell burden improved enhanced insulin sensitivity without affecting body weight or food intake. Mediators of insulin resistance, including inflammatory cytokines and immune cell chemokines, were decreased by targeting senescent cells, while insulin-sensitizing adipogenic transcription factors were increased. Our findings implicate senescence in obesity-related inflammation and metabolic dysfunction. Intermittent treatment with senolytic agents is a potential strategy for treating obesity-related diabetes.