Exercise Modulates High-fat Diet Induced Alterations in Lipid Profiles, Neuropeptides, and Hippocampal Function in Rats

Aim: This study aimed to assess the modulatory effects of exercise on long-term high-fat diet (HFD)-induced variations in lipid parameters, cognitive performance, gut–brain peptides, and hippocampal histopathology in rats. Materials and Methods: Male Wistar albino rats were randomly divided into four experimental groups (n = 10 each): Sedentary-(SED), Exercise-(EX), High-Fat Diet-(HFD), and High-Fat-Diet + Exercise (HFD + EX). Exercise protocol was applied from the 4th weeks of experiment. The Morris Water Maze-(MWM) test was performed at the 4th, 8th, and 12th weeks of experiment to assess spatial learning. Serum levels of lipid profiles (triglyceride-(TG), total cholesterol-(TC), High Density Lipoprotein-(HDL), Low Density Lipoprotein-(LDL)) ghrelin, obestatin, and orexin A/B were measured. Hippocampal tissues were evaluated by hematoxylin–eosin and toluidine blue staining. Group comparisons were evaluated using both parametric (One-Way ANOVA) and non-parametric (Kruskal–Wallis H) statistical tests. Results: Through 6th week of the experiment, both HFD and HFD + EX groups showed lower body weight (p < 0.05). and at 7th week of experiment, only the HFD + EX group remained lighter (p < 0.05). TG, TC and LDL levels were increased in HFD (218.56 ± 57.43, 68.78 ± 12.43, 23.22 ± 4.60 mg/dL) and HFD + EX (159.22 ± 55.15, 70.78 ± 8.07, 26.9 ± 5.16 mg/dL) groups (p < 0.05). Ghrelin was highest in the HFD + EX group (5.58 ± 1.00 ng/mL, p < 0.05), and obestatin levels were decreased in HFD (7.08 ± 0.85 ng/mL) and HFD + EX (7.11 ± 0.45 ng/mL) groups (p < 0.001). Orexin A decreased in the HFD group (2713.38 ± 380.61 pg/mL, p < 0.05), and orexin B was highest in the EX group (7.23 ± 2.21 pg/mL, p < 0.01). MWM test revealed major increase in latency time in the HFD (59 s) group at 12th week of experiment (p < 0.001). Histopathological analysis showed significant hippocampal degeneration, necrosis, and gliosis in HFD and HFD + EX groups (p < 0.001). Conclusion: This study offers a comprehensive evaluation of long-term HFD exposure and exercise by jointly assessing metabolic outcomes, cognition, gut–brain peptides, and hippocampal histopathology—an approach seldom combined in a single design. The findings show that exercise offers limited neuroprotective and metabolic benefits but does not fully prevent HFD-induced hippocampal damage, highlighting a novel multidimensional perspective and pointing to the need for additional protective strategies.