Social stress, obesity and glucose tolerance: a psychobiological investigation

A chronic exposure to stress has been associated with neuroendocrine changes and metabolic disorders including obesity, glucose intolerance and insulin resistance. While these disorders have been identified as underlying causes in the development of pre-diabetes, the extent to which chronic psychological stress might represent a causal factor for the etiology of type2 diabetes has not been well investigated so far. We developed and validated a naturalistic model of chronic subordination stress (CSS). Subordinate mice develop a complex syndrome characterized by up-regulated hypothalamus pituitary adrenocortical (HPA)-axis functioning, behavioral depression-like disorders as well as autonomic and immune-endocrine changes. Importantly, a robust phenotype in stressed mice is the development of hyperphagia that in mice fed a high fat diet (HFD) is associated with vulnerability to obesity. The present study aimed to extend validity of our model to a condition of pre-diabetes onset and identify underlying molecular mechanisms. Subordinate mice showed an increased Corticosterone level compare to Con mice. When fed HFD they developed a severe hyperglycemia, hyperinsulinemia, hyperleptinemia and dyslipidemia, all considered risk factors for T2D. Moreover they showed a remarkable β-cells dysfunction (hyperplasia and increased insulin secretion), hepatic insulin signaling (IRS1, IRS2 reduction),ketoacidosis and impaired HPA axis functionality as observed in diabetic patients. All these results taking together suggested that CPS at HFD can be considered a valid animal model of glucocorticoids-induced T2D. Moreover compare to other animal models the physiological and