Inherited 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) to those who are considered as metabolically healthy obese. The exact mechanisms affecting the health of obese subjects have not yet been discovered. Objective: To clarify whether differences in stress response affect metabolic health. Methods: The study was performed in a selectively bred mouse model of inherited social dominance (Dom) and submissiveness (Sub) which exhibit stress resilience or vulnerability, respectively. Mice were given high fat diet (HFD) or standard diet (STD), followed by physiological, histological and molecular analyses. Results: Obesity was developed in both groups, however HFD-feeding induced hyperleptinemia as well as severe glucose intolerance and insulin resistance in Sub mice, while Dom mice were almost unaffected. Histochemistry analysis revealed pancreatic islets hypertrophy and steatosis in Sub, while these pathologies were absent in Dom mice. Furthermore, steatosis was observed in liver and in intercapsular BAT of Sub, while Dom mice were protected from these consequences of HFD feeding. Additionally, white adipose tissue browning was documented based on histological staining, protein and gene expression of thermogenic genes, in Dom but not in Sub mice. Finally, although lifespan of Sub mice was not impaired by HFD, frailty index was accelerated. Conclusions: Inherited stress vulnerability increases the risk to develop obesity-associated comorbidities. The underlying mechanisms are currently investigated, using interventional studies to ameliorate inflammation as well as other hypotheses-free strategies.