Liraglutide Ameliorates Metabolic Dysfunction Targeting the NRF2 Pathway in Obese Rats Induced by a High-Fat Diet

Background: Obesity, driven largely by high-fat diets, is strongly linked to insulin resistance, dyslipidemia, and oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is very important for keeping the redox balance in cells and guarding against liver damage caused by obesity. Liraglutide, a Glucagon like peptide-1 receptor agonist (GLP-1RA), has demonstrated potential in metabolic control and antioxidant defense. Objective: This study investigated the dose-dependent effects of liraglutide on weight control, glycemic status, lipid profile, and hepatic NRF2 expression in high-fat diet–induced obese rats. Methods: Thirty-five male Wistar rats were divided randomly into five groups: control, high-fat diet (HFD), and three liraglutide-treated groups (100, 200, and 400 µg/kg/day, subcutaneously for 28 days following HFD induction). Body weight, Lee index, fasting glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), lipid parameters, and NRF2 (immunohistochemistry) were assessed. Statistical significance was evaluated by ANOVA with Tukey’s post hoc test. Results: High-fat diet induction caused marked obesity, dyslipidemia, hyperglycemia, hyperinsulinemia, and a sharp reduction in hepatic NRF2 expression. Liraglutide produced clear dose-dependent improvements across all parameters. Body weight and Lee index declined significantly after treatment, with the 400 µg/kg dose nearly restoring normal adiposity. Glycemic indices (glucose, insulin, HOMA-IR) improved progressively, and the highest dose achieved near-normal insulin sensitivity. Lipid abnormalities were corrected, showing increased HDL and reduced LDL, cholesterol, and triglycerides. NRF2 immuno-expression increased markedly in a dose-dependent manner, with the high dose showing the strongest restoration of antioxidant defense. Conclusion: Liraglutide exerts a strong dose-dependent protective effect against HFD-induced obesity and metabolic dysfunction. Its dual action on glycemic control and NRF2-mediated antioxidant defense highlights its therapeutic potential for managing obesity, insulin resistance, and related hepatic complications.