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.

译文

:脂肪组织摄入过多的脂肪酸和葡萄糖会触发脂肪细胞功能障碍和免疫细胞浸润。脂肪组织中代谢稳态的改变会促进胰岛素抵抗,2型糖尿病,高血压和心血管疾病。炎症和代谢过程由共享共同细胞靶标,蛋白酶激活受体2(PAR2)的某些蛋白水解酶介导。这项研究表明,人和大鼠的肥胖症在体内与PAR2在脂肪组织(主要是在包括巨噬细胞的基质血管细胞(SVC))中表达的增加有关。 PAR2在人类巨噬细胞上的表达高于其他PAR,并且通过膳食脂肪酸(棕榈酸,硬脂酸和肉豆蔻酸)增加。以10 mg / kg / d(wk 8-16)口服给予的新型PAR2拮抗剂GB88(5-isoxazoyl-Cha-Ile-spiroindene-1,4-piperidine)在体重减轻的肥胖大鼠中体重减轻了约10% 16周的高碳水化合物高脂(HCHF)饮食,可大大减轻肥胖,脂肪组织炎症,巨噬细胞和肥大细胞浸润,胰岛素抵抗以及心脏纤维化和重塑;同时逆转肝和胰腺功能障碍,并使MIN6β细胞中PAR2指导的葡萄糖刺激的胰岛素分泌正常化。总之,PAR2是肥胖的一种新的生物标志物,它的表达受到饮食脂肪酸的刺激。 PAR2是导致炎症和代谢功能障碍的重要因素。 PAR2拮抗剂可抑制饮食引起的肥胖症以及炎症,代谢和心血管功能障碍。

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