Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice
Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice
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DOI：
10.1172/jci31986
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发表时间：
2007-10-01
影响因子：
15.9
通讯作者：
Bruemmer, Dennis
中科院分区：
文献类型：
--
作者：
Nomiyama, Takashi;Perez-Tilve, Diego;Bruemmer, Dennis
肥胖与一种慢性、低度炎症状态相关，其特征是细胞因子产生异常以及巨噬细胞浸润到脂肪组织中，这可能导致胰岛素抵抗的发展。在免疫反应期间，巨噬细胞对组织的浸润依赖于骨桥蛋白的表达，骨桥蛋白是一种细胞外基质蛋白和促炎细胞因子，可促进单核细胞趋化和细胞运动。在本研究中，我们使用饮食诱导肥胖的小鼠模型来研究骨桥蛋白在肥胖过程中脂肪组织巨噬细胞积聚以及胰岛素抵抗发展中的作用。暴露于高脂肪饮食的小鼠血浆骨桥蛋白水平升高，且在被募集到脂肪组织的巨噬细胞中表达增加。缺乏骨桥蛋白的肥胖小鼠在对饮食诱导的肥胖、身体组成或能量消耗没有影响的情况下，胰岛素敏感性得到改善。这些小鼠还表现出脂肪组织中巨噬细胞浸润减少，这可能反映了巨噬细胞运动能力受损以及基质血管细胞对单核细胞的募集减弱。最后，肥胖的骨桥蛋白缺陷小鼠在脂肪组织和全身的炎症标志物均降低。综上所述，这些结果表明骨桥蛋白可能通过促进炎症以及巨噬细胞在脂肪组织中的积聚，在肥胖与胰岛素抵抗发展之间的联系中起关键作用。
Obesity is associated with a state of chronic, low-grade inflammation characterized by abnormal cytokine production and macrophage infiltration into adipose tissue, which may contribute to the development of insulin resistance. During immune responses, tissue infiltration by macrophages is dependent on the expression of osteopontin, an extracellular matrix protein and proinflammatory cytokine that promotes monocyte chemotaxis and cell motility. In the present study, we used a murine model of diet-induced obesity to examine the role of osteopontin in the accumulation of adipose tissue macrophages and the development of insulin resistance during obesity. Mice exposed to a high-fat diet exhibited increased plasma osteopontin levels, with elevated expression in macrophages recruited into adipose tissue. Obese mice lacking osteopontin displayed improved insulin sensitivity in the absence of an effect on diet-induced obesity, body composition, or energy expenditure. These mice further demonstrated decreased macrophage infiltration into adipose tissue, which may reflect both impaired macrophage motility and attenuated monocyte recruitment by stromal vascular cells. Finally, obese osteopontin-deficient mice exhibited decreased markers of inflammation, both in adipose tissue and systemically. Taken together, these results suggest that osteopontin may play a key role in linking obesity to the development of insulin resistance by promoting inflammation and the accumulation of macrophages in adipose tissue.