Imbalanced inflammatory response promotes obesity-induced metabolic alterations in stress vulnerable mice

The adverse consequences of stress on obesity and associated metabolic abnormalities are well recognized. However, much less is known about metabolic outcomes of stress among individuals with varying stress resiliency. In our previous study, by employing selectively bred socially dominant (Dom) and socially submissive (Sub) mice with inherited resiliency or vulnerability to stress, respectively, we demonstrated that stress vulnerability worsens the metabolic abnormalities induced by high fat diet (HFD). The aim of this study was to investigate the role of inflammation in the susceptibility of Sub mice to obesity comorbidities. Results: HFD induced expression of pro-inflammatory genes in the liver and in epididymal white adipose tissue (eWAT) of Sub mice, while Dom mice were protected from these effects of HFD feeding. Moreover, pro-inflammatory genes were elevated in inguinal WAT (iWAT) of Sub mice even under regimen of standard diet feeding, suggesting fundamental tissue impairment. In order to find whether inflammation is involved in the metabolic alterations observed in obese Sub mice, interventional study was performed, in which Sub and Dom mice were given HFD feeding in the presence or absence of an anti-inflammatory agent (celecoxib, a Cox2 inhibitor). Celecoxib improved glucose tolerance and insulin sensitivity and prevented hepatic and BAT steatosis in HFD-fed Sub mice, while Dom mice were unaffected. In addition, expression of pro-inflammatory markers was modified by celecoxib in adipose tissue of Sub mice. Conclusion: Stress vulnerability, accompanied by an elevated inflammatory state, contribute to higher susceptibility to metabolic alterations.