FASEB J：新的研究表明肥胖是一种炎症性疾病

毒手药王邓智先

导语：科学家证实在超重/肥胖人类和老鼠的腹部脂肪组织中PAR2炎性蛋白的量存在异常。

标签：肥胖  炎症

　　近日，发表在FASEB Journal杂志上的一项新的研究报告中，科学家证实在超重/肥胖人类和老鼠的腹部脂肪组织中PAR2炎性蛋白的量存在异常。研究发现饮食中常见的脂肪酸会增加人免疫细胞表面上的PAR2炎性蛋白。当高糖和高脂肪饮食喂养的肥胖大鼠被给予新的口服药物（药物结合PAR2），这种蛋白引起炎症被抑制，同时高脂肪和高糖饮食引发的其他功效包括肥胖本身也被抑制。
　　新研究证实：旨在阻止某些炎症蛋白的药物，可能能够预防和治疗肥胖，肥胖又是2型糖尿病，心脏疾病，中风，肾衰竭和癌症的主要危险因素。Fairlie和他的同事发现第一个强效，选择性和口服的小分子PAR2拮抗剂，在炎症细胞模型和动物模型中阐述了其特点及其功能反应。
　　他们发现，PAR2的表达在肥胖人类和大鼠体内脂肪组织中增加；在体外，膳食中脂肪酸棕榈酸刺激人巨噬细胞PAR2表达增高；PAR2拮抗剂抑制在体内和体外都能抑制PAR2的表达。拮抗剂随即用来作为一种工具来剖析PAR2的激活在调节人单核细胞来源的巨噬细胞（HMDM） 代谢紊乱等中的作用。
　　口服PAR2拮抗剂治疗饮食诱导的肥胖大鼠能抑制脂肪组织PAR2信号，抑制脂肪炎症，胰岛素抵抗，膳食诱导的肥胖和心血管异常。这是首个研究证实PAR2拮抗剂能改善肥胖，葡萄糖稳态和体内肥胖相关的慢性炎症。这些结果表明，增加PAR2表达可能是判断代谢功能障碍新的生物标志物，即PAR2拮抗作用可用于治疗代谢紊乱和肥胖症。

原文阅读：Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism
Abstract
Excessive uptake of fatty acids and glucose by adipose tissue triggers adipocyte dysfunction and infiltration of immune cells. Altered metabolic homeostasis in adipose tissue promotes insulin resistance, type 2 diabetes, hypertension, and cardiovascular disease. Inflammatory and metabolic processes are mediated by certain proteolytic enzymes that share a common cellular target, protease-activated receptor 2 (PAR2). This study showed that human and rat obesity correlated in vivo with increased expression of PAR2 in adipose tissue, primarily in stromal vascular cells (SVCs) including macrophages. PAR2 was expressed more than other PARs on human macrophages and was increased by dietary fatty acids (palmitic, stearic, and myristic). A novel PAR2 antagonist, GB88 (5-isoxazoyl-Cha-Ile-spiroindene-1,4-piperidine), given orally at 10 mg/kg/d (wk 8–16) reduced body weight by ?10% in obese rats fed a high-carbohydrate high-fat (HCHF) diet for 16 wk, and strongly attenuated adiposity, adipose tissue inflammation, infiltrated macrophages and mast cells, insulin resistance, and cardiac fibrosis and remodeling; while reversing liver and pancreatic dysfunction and normalizing secretion of PAR2-directed glucose-stimulated insulin secretion in MIN6 β cells. In summary, PAR2 is a new biomarker for obesity, and its expression is stimulated by dietary fatty acids; PAR2 is a substantial contributor to inflammatory and metabolic dysfunction; and a PAR2 antagonist inhibits diet-induced obesity and inflammatory, metabolic, and cardiovascular dysfunction.—Lim, J. Iyer A., Liu L., Suen J. Y., Lohman R.-J., Seow V., Yau M.-K., Brown, L., Fairlie, D. P. Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism.

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PAR2拮抗剂能改善肥胖，

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