Early Cognitive and Hippocampal Alterations During Diet-Induced Metabolic Dysfunction in Sprague–Dawley Rats

Abstract Background Diet-induced obesity and insulin resistance are associated with an increased risk of cognitive impairment, yet the onset of these changes before overt type 2 diabetes (T2DM) remains poorly understood. This study investigated cognitive and hippocampal alterations associated with diet-induced metabolic dysfunction in a pre-diabetic rat model. Methods Forty-eight male and female Sprague–Dawley rats were fed either a high-fat diet (HFD) with fructose water or a regular diet for 21 weeks. Behavioural assessments were performed after 15 weeks of dietary intervention, before streptozotocin (STZ) administration, to evaluate cognitive function during the pre-diabetic stage. Metabolic parameters were measured throughout the study, and hippocampal and serum biomarkers of neurodegeneration, oxidative stress, and neuroplasticity were analysed at the study endpoint. Results HFD significantly increased body weight, fasting blood glucose, and insulin resistance (all P < 0.0001). Behavioural testing revealed impaired long-term memory consolidation without affecting spatial learning. Hippocampal analysis demonstrated increased MMP-9, phosphorylated tau, and β-amyloid levels, indicating early neurodegenerative changes. Unexpectedly, hippocampal BDNF levels were elevated in HFD male rats ( P < 0.05), suggesting a potential compensatory response during early metabolic dysfunction. Conclusion Diet-induced metabolic dysfunction was associated with early cognitive impairment and hippocampal molecular alterations before the development of overt T2DM. These findings suggest that metabolic disturbances may initiate neurobiological changes preceding clinical diabetes and support the existence of an early window for intervention.