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

Danbi Jo,Gwangho Yoon,Juhyun Song

doi:10.3390/antiox10010078

Abstract

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.

Highlights

Metabolic syndrome is a major global health issue, and is gradually increasing in prevalence worldwide, at all ages [1]
We investigated whether apoptosis response was suppressed by Ex-4 in palmitic acid (PA)-treated neurons (Figure 1)
Our data showed that the expression of pro-apoptotic genes, such as apoptotic peptidase activating factor 1 (APAF1) and BCL2-associated agonist of cell death (BAD) were increased, whereas those of anti-apoptotic genes such as BCL2 like 1 (BCL2L1), myeloid cell leukemia sequence

Summary

Introduction

Metabolic syndrome is a major global health issue, and is gradually increasing in prevalence worldwide, at all ages [1]. Obesity is one of these metabolic syndromes, and is rapidly growing in incidence; obesity is accompanied by dyslipidemia, hypertension, diabetes, and cognitive dysfunction [2]. Hyperglycemia in obesity causes vascular damage, brain atrophy, and impaired neurogenesis in the brain [5]. It has been shown to increase the risk of Alzheimer’s disease (AD) by promoting severe neuroinflammation, insulin resistance, synaptic dysfunction, and impairments in cerebral vasculature [6]. Obese patients showed brain insulin resistance, increased neuroinflammation response, and excessive saturated fatty acids, such as palmitate, both in circulation and the cerebrospinal fluid [7,8]

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