Study On The Mechanism Of Hypothalamic Insulin Resistance Was Caused By Urea-induced Damage

Objective:To investigate the effect of urea on the insulin sensitivity was regulated by central nervous system and the mechanism of insulin resistance in brain liver axis.Methods:1.To establish the animal model for urea damaging to the hypothalamic center of mice.The mice were randomly divided into two groups:mice was infused with urea or artificial cerebrospinal fluid through the third ventricle(ICV)for 48 hours,then injected with insulin,the related insulin signaling pathway,inflammation,oxidative stress and endoplasmic reticulum stress(ER stress)were detected in hypothalamus and other tissues.2.To demonstrate the mechanism of insulin resistance was induced by urea.The mice were divided into two groups and injected with MnTBAP or saline for 3 days,then the above two groups were divided into four groups:(1)control+insulin group(C+I group);(2)urea+insulin group(U+I Group);(3)control+antioxidant+insulin group(C+M+I group);(4)urea+antioxidant+insulin group(U+M+I group),and the indicators were detected again in the same way.Results:1.The animal model of central metabolic system damaged by urea was successfully established.Urea inhibited insulin-induced phosphorylation of protein kinase B(p-AKT473)in hypothalamus,liver and muscle tissues through ICV infusion(down 41.83%,25.26%and 42.60%,respectively,P<0.05).2.Urea induced reactive oxygen species(ROS)in hypothalamus(increased by 63.77%,P<0.05).3.Urea induced phosphorylationof NF-κBp65 in hypothalamus and liver tissues(increased by 141.24%,35.11%,respectively,P<0.05),and increased mRNA expression of inflammatory factors TNF-α,IL-1β,and IL-6(increased by 329.14%,1091.03%,3167.12%,respectively,P<0.05)and increased ER stress(such as Xbp1-spliced increased by 169.74%,P<0.05)in hypothalamus.4.Antioxidants could prevent urea induced damage(P<0.05).Conclusion:ICV infusion of urea can damage the central metabolism regulation of hypothalamus,and reduced expression of p-Akt473,which resulting in insulin resistance in the brain-peripheral,especially in the brain-liver axis.At the same time,urea can increase ROS level andactivate the NF-κB signaling pathwayin turn,increase inflammatory factors and ER stress markers,antioxidants have a preventive effect on this.These results suggest that urea activated oxidative stress is one of the mechanisms for insulin resistance of brain-liver axis.