Determining the effect of lipid nanoemulsions on insulin signaling and the inflammatory pathways at the Blood-Brain Barrier

Abstract

Several studies have shown that metabolic disorders such as type-2 diabetes (T2DM) play a role in propagating neurodegenerative disorders like Alzheimer’s Disease (AD)(1). As the brain is an insulin-sensitive organ and requires insulin for promoting neuronal integrity and function, impairment of insulin signaling in the CNS has huge implications for memory and cognition(2). Hyperinsulinemia observed in AD and T2DM contributes to vascular inflammation, which in turn, leads to endothelial insulin resistance by impairing insulin receptor (IR) and insulin resistance substrate (IRS)-1(1). The insulin resistance leads to a compensatory increase in circulating insulin leading to hyperinsulinemia. In addition to the impairment of insulin signaling, another hallmark of AD is lipid dysfunction(3). The lipid bilayer of the Blood-Brain Barrier (BBB) endothelial cells harbors lipid rafts that play a vital role in transcytosis and maintaining various signaling functions(3). Lipid metabolism at the BBB changes with age and diet and results in a decrease of unsaturated fatty acid content and an increase in lipid peroxidation. In this study, we hypothesize that the delivery of lipid nanoemulsion, which is rich in unsaturated fatty acids, will improve insulin signaling at the BBB, and ameliorate insulin resistance caused by cytokines like TNF-α. This, in turn, is expected to decrease VCAM-1 expression and mitigate BBB dysfunction. This hypothesis has been verified by treating BBB endothelial cells with inflammatory cytokines like TNF-α, which inhibited insulin signaling and increase the expression of vascular cell adhesion molecule-1 (VCAM-1), a marker for endothelial inflammation. Alternatively, exposure to soybean oil nanoemulsion (SNEs) like that of Humulin® triggered insulin signaling and reduced VCAM-1 expression. The results showed that the SNEs have the ability to overcome the resistance induced by TNF-α, and increased the insulin signaling to the level comparable to Humulin® control and the opposite effect was seen when the cells were treated with nanoemulsion rich in saturated fatty acids. Lipid-based nanoemulsion could be used as a strategy to mitigate insulin resistance and the consequent inflammation commonly seen in neurodegenerative disorders like AD.