Social Stress Increases Vulnerability to High-Fat Diet-Induced Insulin Resistance by Enhancing Neutrophil Elastase Activity in Adipose Tissue

Social stress (SS) has been linked to the development of cardiovascular disease (CVD), which is closely associated with insulin resistance (IR); however, the causal effect of SS on IR remains unclear. The 8-week-old male C57BL/6 mice were exposed to SS by housing with a larger CD-1 mouse in a shared home cage without physical contact for 10 consecutive days followed by high-fat diet (HFD) feeding. Control mice were housed in the same cage without a CD-1 mouse. After 6 weeks of HFD, insulin sensitivity was significantly impaired in stressed mice. While the percentage of classically activated macrophages in epididymal white adipose tissue (eWAT) was equivalent between the two groups, the percentage of lymphocyte antigen 6 complex locus G6D (Ly-6G)/neutrophil elastase (NE)-double positive cells markedly increased in stressed mice, accompanied by augmented NE activity assessed by ex vivo eWAT fluorescent imaging. Treatment with an NE inhibitor completely abrogated the insulin sensitivity impairment of stressed mice. In vitro NE release upon stimulation with a formyl peptide receptor 1 agonist was significantly higher in bone marrow neutrophils of stressed mice. Our findings show that SS-exposed mice are susceptible to the development of HFD-induced IR accompanied by augmented NE activity. Modulation of neutrophil function may represent a potential therapeutic target for SS-associated IR.