AMPK-PPARα-CD36 Axis Mediates Berberine's Amelioration of Olanzapine-Induced Lipid Dysregulation in Mice

Introduction: While olanzapine is an effective atypical antipsychotic, its clinical application is limited by adverse effects such as weight gain and lipid metabolism disorders. Berberine, a natural compound known for its lipid-lowering and anti-inflammatory properties, presents a potential therapeutic strategy to counteract these issues. Therefore, this study aimed to explore the ameliorative impact of berberine on olanzapine-induced lipid metabolism disorders in mice, with a specific focus on the AMPK–PPARα–CD36 signaling axis. materials and methods: Male C57 mice were divided into control, olanzapine, and olanzapine + berberine groups, treated for 6 weeks. Plasma TG, TC, HDL-C, and LDL-C were measured. Liver tissues were stained for lipid accumulation. Hub genes were identified through PubMed searches, differential analysis, weighted gene co-expression network analysis, and SVM-RFE. Protein expressions of AMPK, p-AMPK, PPARα, and CD36 were assessed by Western blot. Methods: Male C57 mice were divided into control, olanzapine, and olanzapine + berberine groups, treated for 6 weeks. Plasma TG, TC, HDL-C, and LDL-C were measured. Liver tissues were stained for lipid accumulation. Hub genes were identified through PubMed searches, differential analysis, weighted gene co-expression network analysis, and SVM-RFE. Protein expressions of AMPK, p-AMPK, PPARα, and CD36 were assessed by Western blot. Results: Olanzapine increased plasma TG and HDL-C, decreased TC and LDL-C, and caused hepatic lipid accumulation. It also downregulated AMPK/p-AMPK and PPARα, while upregulating CD36. Berberine reversed these effects, lowering TG, partially restoring TC and LDL-C, reducing liver lipid deposition, increasing AMPK/p-AMPK and PPARα, and inhibiting CD36 expression. Discussion: Olanzapine-induced lipid dysregulation may be mediated by the inhibition of AMPK and PPARα and the upregulation of CD36. Berberine effectively reversed these changes by activating the AMPK-PPARα pathway and inhibiting CD36 expression, thereby improving hepatic lipid accumulation. These findings suggest that berberine may serve as a potential adjunctive therapy for alleviating olanzapine-induced metabolic side effects. Conclusion: Olanzapine induces lipid disorders by inhibiting AMPK, reducing PPARα, and upregulating CD36, enhancing lipid uptake and impairing fatty acid oxidation. Berberine ameliorates these abnormalities by activating AMPK–PPARα signaling and suppressing CD36, highlighting its potential as an adjunctive therapy to mitigate olanzapine-induced metabolic side effects.