EXENDIN-4 IMPROVES NEURONAL CELL SURVIVAL AND AXON GROWTH IN HIGH FAT HIGH CHOLESTEROL MOUSE

high-fat, high-cholesterol (HFHC) diet contributes to insulin resistance and chronic inflammation, which are major risk factors for metabolic disorders such as obesity. HFHC intake also promotes neuroinflammation, cognitive dysfunction, and neurodegenerative changes in the central nervous system (CNS). In the brain, HFHC impairs neuronal functions involved in learning and memory. Exendin-4 (Ex-4), a glucagon-like peptide-1 (GLP-1) receptor agonist, is well known for its ability to reduce inflammatory responses, improve insulin sensitivity, and enhance neuronal complexity and synaptic plasticity. Metabolic imbalance induced by HFHC is accompanied by increased secretion of inflammatory cytokines and adipokines. Activated microglia in response to HFHC release proinflammatory cytokines and chemokines, thereby exacerbating neuronal inflammation. In this study, Ex-4 was administered intraperitoneally at a dose of 5 μg/kg/day once daily for 5 weeks to investigate its effects on the brains of HFHC-fed mice. We further examined whether Ex-4 treatment improved memory function in HFHC mice using the T-maze test. Subsequently, cortical tissue was analyzed by RNA sequencing to identify genes with altered expression. We observed significant changes in the expression of genes associated with actin filaments and microtubules in the brains of HFHC-fed mice injected with Ex-4. In addition, Ex-4 pretreatment in BV-2 microglial cells reduced the secretion of proinflammatory cytokines and attenuated neuronal damage in Neuro-2A neuronal cells. Collectively, our data suggests that Ex-4 modulates neuronal function by regulating HFHC-induced neuroinflammation.