Endothelial mineralocorticoid receptors in diet-induced skeletal muscle insulin resistance

项目摘要/摘要 过多的脂类增加了细胞内总脂质含量和异位脂肪储存，导致 胰岛素及其作用的主要靶点之一--骨骼肌脂毒性和胰岛素抵抗 是维持葡萄糖动态平衡的中心。摄入高脂肪和精制糖的饮食， 西方饮食(WD)，激活盐皮质激素受体(MRS)，诱导肌肉脂代谢紊乱 胰岛素抵抗。最近的数据进一步表明，细胞特异性内皮细胞(EC)MR(ECMR)激活 介导WD诱导的肌肉脂代谢紊乱、受损的胰岛素代谢信号和组织 胰岛素抵抗。在这方面，eCMR激活增加了骨骼肌小动脉和骨骼肌微动脉中CD36的表达 组织，这促进了肌肉血管系统中过度的游离脂肪酸运输，导致骨骼 肌肉脂肪堆积、CD36棕榈酰化和胰岛素抵抗。两者之间存在着一种关系 微血管内皮细胞功能障碍与肌肉代谢紊乱和胰岛素抵抗 外显体。最近的数据表明，EC衍生的胞外体蛋白，如胞外体CD36，可以促进 脂肪堆积和代谢紊乱。一旦从内皮细胞中释放出来，外体CD36就可以被摄取 通过邻近的骨骼肌，从而促进肌肉脂肪堆积。这是一个假设 应用是激活ECMRs诱导EC CD36表达和EC衍生的释放 胞外体CD36增加内皮细胞对游离脂肪酸的摄取和向骨骼肌的转位 导致骨骼肌肌细胞内脂质沉积和胰岛素抵抗。目标1 本研究旨在了解eCMR信号在CD36、游离脂肪表达中的作用和机制 内皮细胞和骨骼肌细胞的酸摄取，以及相关的肌肉脂肪沉积和胰岛素抵抗。 本应用的目的2是研究增强型eCMR信号转导通路在血管内皮细胞生长中的作用和机制。 EC来源的胞外体CD36的释放及其在促进骨骼肌细胞CD36进一步增加中的作用 促进肌肉脂肪酸摄取、IMC脂肪沉积和胰岛素抵抗。相应地，体外细胞处理 用游离脂肪酸和体内饲喂WD的小鼠建立eCMR/ECCD36激活模型， 肥胖和胰岛素抵抗。拟议的工作应使人们更好地了解环境管理专家的作用。 而EC胞外体CD36在骨骼肌胰岛素抵抗的发生发展中提供了重要的作用 用于早期诊断和预防这一日益增长的糖尿病原因的生物标志物。

Project Summary/Abstract Excess lipids increase the total intramyocellular lipid content and the ectopic fat storage resulting in lipotoxicity and insulin resistance in skeletal muscles, which is one of the main targets of insulin and its action is central for the maintenance of glucose homeostasis. Consumption of a diet high in fat and refined sugars, a Western Diet (WD), activates mineralocorticoid receptors (MRs) to induce muscle lipid metabolic disorders and insulin resistance. Recent data further indicate that cell specific endothelial cell (EC) MR (ECMR) activation mediates WD-induced muscle lipid metabolism disorders, impaired insulin metabolic signaling, and tissue insulin resistance. In this regard, ECMR activation increase CD36 expression in skeletal muscle arterioles and tissues, which promotes excessive free fatty acid trafficking across the muscle vasculature, leading to skeletal muscle lipid accumulation, CD36 palmitoylation and insulin resistance. There is a relationship between microvascular endothelial dysfunction and muscle metabolic disorders and insulin resistance through exosomes. Recent data suggest that EC derived exosomal proteins, such as exosomal CD36, can promote lipid accumulation and metabolic disorders. Upon being released from ECs, exosomal CD36 can be up-taken by the neighboring skeletal muscle and thus promote muscle lipid accumulation. The hypothesis of this application is that activation of ECMRs induces EC CD36 expression and release of EC-derived exosomal CD36 which increases free fatty acid uptake in ECs and translocation to skeletal muscle cells, leading to skeletal muscle intramyocellular lipid deposits and insulin resistance. Objective 1 of this application is to understand the role and mechanisms of ECMR signaling on CD36 expression, free fatty acid uptake in ECs and skeletal muscle cells, and related muscle lipid deposition and insulin resistance. Objective 2 of this application is to investigate the role and mechanisms of enhanced ECMR signaling on the EC-derived exosomal CD36 release and its role in facilitating increased skeletal muscle cell CD36 to further promote muscle fatty acid uptake, IMC lipid deposition and insulin resistance. Accordingly, in vitro cell treated with free fatty acid and in vivo mice fed a WD will be used to set up a model of ECMR/ECCD36 activation, obesity and insulin resistance. The proposed work should provide a better understanding the role of ECMRs and EC exosomal CD36 in the development of skeletal muscle insulin resistance and provide an important biomarker for the early diagnosis and prevention of this increasing cause of diabetes.