Uncovering altered neural molecular mechanisms in metabolic disorders induced psychiatric disorders

Lifestyle changes involving high caloric diet, sedentary life, and/or persistent stress appear to play a role in the onset of metabolic syndrome (MetS), which is characterized by hyperglycemia, hyperinsulinemia, dyslipidemia, obesity, and type-2 diabetes. MetS in the long run appears to have cerebrovascular consequences, resulting in neuropsychiatric disorders. However, there is a paucity of molecular studies using relevant animal models of metabolic disorder-induced neuropsychiatric disorders. Here, we tried to model the clinical conditions of MetS by feeding C57bl/6 Ncrl mice a high fructose diet (Hfr) for almost 12 months. Random glucose, fasting glucose, glucose tolerance, and triglycerides did not differ significantly between the Hfr diet and Control diet (Cont) groups even after a year on the Hfr diet, except for the accelerated aging-like phenotype in coat color and shiny texture. However, exposure to chronic stress for a week induced metabolic disorder as reflected in high post-prandial blood glucose in the Hfr group, and subsequently mood disorder (depression and anxiety) (p<0.01) and cognitive disorder (p<0.01) as indicated by the behavioral tests. To uncover the underlying molecular mechanisms in the prefrontal cortex, a transcriptomic study was performed. The data analysis revealed hundreds of differentially expressed genes (DEGs) between the groups (i.e., HfrUST vs CoUST = 348 genes; CoST vs CoUST = 496 genes; HfrST vs HfrUST =226 genes and HfrST vs CoST= 18 genes). The pattern of gene expression was strikingly different in the HfrST group compared to the Ctrl group, thus correlating the phenotype, i.e. MetS induced mood and cognitive disorders. Pathway analysis of the DEGs indicated perturbations in cellular metabolism, inflammation, innate immunity, neurogenesis, vasculogenesis, ion channels, and neuronal signaling. In addition, altered epigenetic regulators appear to mediate the stress-induced precipitation of metabolic and neuropsychiatric disorders. The outcome of our study supports the hypothesis of disease susceptibility due to lifestyle changes involving a high-calorie diet and chronic stress.