Nomiyama Takashi, Perez-Tilve Diego, Ogawa Daisuke, Gizard Florence, Zhao Yue, Heywood Elizabeth B, Jones Karrie L, Kawamori Ryuzo, Cassis Lisa A, Tschöp Matthias H, Bruemmer Dennis
Division of Endocrinology and Molecular Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
J Clin Invest. 2007 Oct;117(10):2877-88. doi: 10.1172/JCI31986.
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.
肥胖与一种慢性低度炎症状态相关，其特征为细胞因子产生异常以及巨噬细胞浸润脂肪组织，这可能有助于胰岛素抵抗的发展。在免疫反应过程中，巨噬细胞的组织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性和细胞运动。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期间脂肪组织巨噬细胞积累和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，在募集到脂肪组织中的巨噬细胞中表达也升高。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无影响的情况下，胰岛素敏感性得到改善。这些小鼠进一步证明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受损以及基质血管细胞单核细胞募集减弱。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和脂肪组织中巨噬细胞的积累，在将肥胖与胰岛素抵抗的发展联系起来方面发挥关键作用。
