Intermittent High-Fructose Corn Syrup Consumption Induces Hippocampal Degeneration and Orexin Dysregulation Despite Moderate Exercise Training

Abstract Background High-fructose corn syrup-(HFCS) consumption has been associated with metabolic disturbances and cognitive dysfunction. This study investigated whether moderate-intensity exercise could attenuate HFCS-induced metabolic and hippocampal alterations in rats. Methods Thirty-two male Sprague–Dawley rats were randomly assigned to four groups (n = 8): control-(CON), exercise-(EX), HFCS, and HFCS+exercise-(HFCS + EX). HFCS-treated rats received a 20% (w/v) HFCS solution on three non-consecutive days per week for 8 weeks. Exercise groups underwent moderate-intensity treadmill exercise for 8-weeks. Body weight, oral-glucose-tolerance-test-(OGTT), serum insulin, orexin-A, and orexin-B levels were assessed. Behavioral performance was evaluated using the Open-Field-Test and Morris-Water-Maze during the 1st, 4th, and 8th weeks of the experimental period. Hippocampal regional volumes were quantified using ImageJ-software, and histopathological changes in the CA1-CA3-dentate-gyrus-(DG) regions were evaluated using hematoxylin–eosin-(H&E) and toluidine-blue-(TB) staining. Results HFCS consumption did not significantly affect body weight or fasting serum insulin levels but impaired glucose tolerance, by elevated blood glucose concentrations at 120 min during the OGTT. Serum orexin-A and orexin-B levels were significantly reduced in HFCS-treated rats, whereas exercise alone significantly increased both peptides. Behavioral alterations, with no significant locomotor impairment and only limited deficits in spatial learning. Histopathological analysis revealed marked neuronal degeneration, necrosis, gliosis, reduced Nissl body density, and significant volume loss in the CA1,CA3, and DG regions following HFCS exposure. Conclusion Intermittent HFCS consumption induced early metabolic and hippocampal dysfunction characterized by impaired glucose tolerance, reduced circulating orexin levels, and hippocampal neurodegeneration despite preserved body weight and serum-insulin levels. Moderate-intensity-exercise provided only partial neuroprotection against HFCS-induced alterations.