Stress Vulnerability Increases the Severity of Obesity-induced Metabolic Alterations in HFD-fed Mice

Introduction:
Obesity is a risk factor for development of cardio-metabolic disease, however a high metabolic heterogeneity exists among individuals with the same BMI, ranging between a subgroup of highly-affected subjects (metabolically unhealthy obese, MUO) to those who are considered as metabolically healthy obese (MHO). The exact mechanisms affecting the metabolic health of obese subjects have not yet been discovered.

Objective:
To clarify whether differences in stress response determine the metabolic health of obese mice. Methods: The study was performed in a mouse model of social dominance (Dom) and submissiveness (Sub) which also relates to differing levels of stress sensitivity. Mice were given high fat diet (HFD) or standard diet (STD) for 8 weeks, followed by physiological, histological and molecular analyses.

Results:
Obesity was developed in both groups, however HFD-feeding induced hyperleptinemia and a severe glucose intolerance and insulin resistance in Sub mice, while Dom mice were almost unaffected. Histochemistry analysis revealed pancreatic islets hypertrophy and pancreatic steatosis in Sub mice, with a lower severity of such pathologies in Dom mice. In addition, Dom mice were protected from HFD-induced hepatic steatosis, which was observed in Sub mice. Adipocyte hypertrophy and altered expression of adipocytokines was observed in STD-fed Sub mice, suggesting that stress vulnerability lead to dysfunction of adipose tissue.

Conclusions:
Stress vulnerability increases the risk to develop MUO. Mapping the protective mechanisms that promote MHO is important for the development of treatment strategies to reduce the risk for obesity-associated comorbidity diseases in obese individuals.