Endothelial mineralocorticoid receptors in diet-induced skeletal muscle insulin resistance

饮食诱导的骨骼肌胰岛素抵抗中的内皮盐皮质激素受体

• 批准号: 10308420
• 负责人: Guanghong Jia
• 金额: $ 39.7万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10308420
• 关键词: Adipocytes; Aldosterone; Biochemical Pathway; Blood Vessels; CD36 gene; Carbohydrates; Cell membrane; Cells; Consumption; Data; Deposition; Diabetes Mellitus; Diabetes prevention; Diet; Disease; Docking; Early Diagnosis; Endothelial Cells; Endothelium; Enhancers; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Gene Expression; High Fat Diet; Impairment; In Vitro; Insulin; Insulin Resistance; Lead; Lipids; Maintenance; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; MicroRNAs; Mineralocorticoid Receptor; Modeling; Multivesicular Body; Mus; Muscle; Muscle Fibers; Muscle function; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Organ; Pathogenesis; Physiological; Plasma; Prevention; Protein Family; Proteins; Receptor Activation; Receptor Signaling; Renin-Angiotensin-Aldosterone System; Risk Factors; Role; Signal Transduction; Skeletal Development; Skeletal Muscle; Tissues; Transcription Factor AP-1; Vascular Endothelial Cell; Vascular blood supply; Work; arteriole; blood glucose regulation; early detection biomarkers; endothelial dysfunction; exosome; glucose metabolism; hormone regulation; in vivo; insulin sensitivity; intercellular communication; lipid metabolism; macrophage; palmitoylation; paracrine; promoter; receptor expression; recruit; response; saturated fat; skeletal muscle metabolism; sugar; trafficking; translocase; uptake; western diet

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.

项目总结/摘要 过量的脂质增加了总的肌细胞内脂质含量和异位脂肪储存，导致 骨骼肌是胰岛素及其作用的主要靶点之一， 是维持葡萄糖稳态的核心。食用高脂肪和精制糖的饮食， 西方饮食（WD）激活盐皮质激素受体（MR）以诱导肌肉脂质代谢紊乱， 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诱导的肌肉脂质代谢紊乱，受损的胰岛素代谢信号传导， 胰岛素抵抗在这方面，ECMR激活增加了骨骼肌小动脉中的CD 36表达， 组织，这促进了过量的游离脂肪酸运输通过肌肉脉管系统，导致骨骼肌 肌肉脂质积累、CD 36棕榈酰化和胰岛素抵抗。之间存在关系 微血管内皮功能障碍和肌肉代谢紊乱以及胰岛素抵抗 外来体。最近的数据表明，EC衍生的外泌体蛋白，如外泌体CD 36，可以促进 脂质积累和代谢紊乱。当从EC释放时，外泌体CD 36可以被摄取 通过邻近的骨骼肌，从而促进肌肉脂质积累。这个假设 ECMR的激活诱导EC CD 36表达和EC衍生的CD 36的释放， 外泌体CD 36，增加EC中游离脂肪酸的摄取并转运至骨骼肌 细胞，导致骨骼肌肌细胞内脂质沉积和胰岛素抵抗。目标1 本申请旨在了解ECMR信号转导对CD 36表达、游离脂肪酸和细胞凋亡的作用和机制。 EC和骨骼肌细胞的酸摄取，以及相关的肌肉脂质沉积和胰岛素抵抗。 本申请的目的2是研究增强的ECMR信号传导对细胞凋亡的作用和机制。 EC来源的外泌体CD 36释放及其在促进骨骼肌细胞CD 36进一步增加中的作用 促进肌肉脂肪酸摄取、IMC脂质沉积和胰岛素抵抗。因此，体外细胞处理 用游离脂肪酸和体内饲喂WD的小鼠将用于建立ECMR/ECCD 36活化的模型， 肥胖和胰岛素抵抗。拟议的工作应使人们更好地理解ECMR的作用 和EC外泌体CD 36在骨骼肌胰岛素抵抗的发展中提供了重要的 作为早期诊断和预防这种日益增加的糖尿病病因的生物标志物。