Overnutrition Induced Cognitive Impairment: Insulin Resistance, Gut-Brain Axis, and Neuroinflammation

Overnutrition-related obesity has become a worldwide epidemic, and its prevalence is expected to steadily rise in the future. It is widely recognized that obesity exerts negative impacts on metabolic disorders such as type 2 diabetes mellitus (T2DM) and cardiovascular diseases. However, relatively fewer reports exist on the impairment of brain structure and function, in the form of memory and executive dysfunction, as well as neurogenerative diseases. Emerging evidence indicates that besides obesity, overnutrition diets independently induce cognitive impairments via multiple mechanisms. In this study, we reviewed the clinical and preclinical literature about the detrimental effects of obesity or high-nutrition diets on cognitive performance and cerebral structure. We mainly focused on the role of brain insulin resistance (IR), microbiota-gut-brain axis, and neuroinflammation. We concluded that before the onset of obesity, short-term exposure to high-nutrition diets already blunted central responses to insulin, altered gut microbiome composition, and activated inflammatory mediators. Overnutrition is linked with the changes in protein expression in brain insulin signaling, leading to pathological features in the brain. Microbiome alteration, bacterial endotoxin release, and gut barrier hyperpermeability also occur to trigger mental and neuronal diseases. In addition, obesity or high-nutrition diets cause chronic and low-grade systematic inflammation, which eventually spreads from the peripheral tissue to the central nervous system (CNS). Altogether, a large number of unknown but potential routes interact and contribute to obesity or diet-induced cognitive impairment. The challenge for future research is to identify effective interventions involving dietary shifts and personalized therapy targeting the underlying mechanisms to prevent and improve cognition deficits.