Role of Exendin-4 in Brain Insulin Resistance, Mitochondrial Function, and Neurite Outgrowth in Neurons under Palmitic Acid-Induced Oxidative Stress

• Main Authors: Danbi Jo (Author), Gwangho Yoon (Author), Juhyun Song (Author)
• Format: Book
• Published: MDPI AG, 2021-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antiox10010078; 2076-3921
• Keywords: exendin-4 (Ex-4); glucagon like petide-1 (GLP-1); neuronal structure; obesity; palmitic acid (PA); Therapeutics. Pharmacology; RM1-950
• Source: Antioxidants, Vol 10, Iss 1, p 78 (2021)

Glucagon like peptide 1 (GLP-1) is an incretin hormone produced by the gut and brain, and is currently being used as a therapeutic drug for type 2 diabetes and obesity, suggesting that it regulates abnormal appetite patterns, and ameliorates impaired glucose metabolism. Many researchers have demonstrated that GLP-1 agonists and GLP-1 receptor agonists exert neuroprotective effects against brain damage. Palmitic acid (PA) is a saturated fatty acid, and increases the risk of neuroinflammation, lipotoxicity, impaired glucose metabolism, and cognitive decline. In this study, we investigated whether or not Exentin-4 (Ex-4; GLP-1 agonist) inhibits higher production of reactive oxygen species (ROS) in an SH-SY5Y neuronal cell line under PA-induced apoptosis conditions. Moreover, pre-treatment with Ex-4 in SH-SY5Y neuronal cells prevents neural apoptosis and mitochondrial dysfunction through several cellular signal pathways. In addition, insulin sensitivity in neurons is improved by Ex-4 treatment under PA-induced insulin resistance. Additionally, our imaging data showed that neuronal morphology is improved by EX-4 treatment, in spite of PA-induced neuronal damage. Furthermore, we identified that Ex-4 inhibits neuronal damage and enhanced neural complexity, such as neurite length, secondary branches, and number of neurites from soma in PA-treated SH-SY5Y. We observed that Ex-4 significantly increases neural complexity, dendritic spine morphogenesis, and development in PA treated primary cortical neurons. Hence, we suggest that GLP-1 administration may be a crucial therapeutic solution for improving neuropathology in the obese brain.