MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity
MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity
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DOI：
10.1172/jci26498
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发表时间：
2006-06-01
影响因子：
15.9
通讯作者：
Kasuga, Masato
中科院分区：
文献类型：
--
作者：
Kanda, Hajime;Tateya, Sanshiro;Kasuga, Masato
脂肪细胞分泌多种生物活性分子，影响其他组织的胰岛素敏感性。我们现在发现，在遗传性肥胖糖尿病（db/db）小鼠和高脂饮食诱导肥胖的WT小鼠中，脂肪组织中单核细胞趋化蛋白-1（MCP-1）mRNA的丰度和MCP-1的血浆浓度均增加。在aP 2基因启动子的控制下在脂肪组织中表达MCP-1转基因的小鼠表现出胰岛素抵抗、巨噬细胞浸润到脂肪组织中以及增加的肝脏甘油三酯含量。此外，与WT动物相比，MCP-1纯合KO小鼠中由高脂饮食诱导的胰岛素抵抗、肝脂肪变性和脂肪组织中巨噬细胞积聚广泛减少。最后，MCP-1显性负突变体的急性表达改善了db/db小鼠和高脂饮食WT小鼠的胰岛素抵抗。这些发现表明，MCP-1在脂肪组织中表达的增加有助于巨噬细胞浸润到该组织中，胰岛素抵抗和与小鼠肥胖相关的肝脂肪变性。
Adipocytes secrete a variety of bioactive molecules that affect the insulin sensitivity of other tissues. We now show that the abundance of monocyte chemoattractant protein-1(MCP-1) mRNA in adipose tissue and the plasma concentration of MCP-1 were increased both in genetically obese diabetic (db/db) mice and in WT mice with obesity induced by a high-fat diet. Mice engineered to express an MCP-1 transgene in adipose tissue under the control of the aP2 gene promoter exhibited insulin resistance, macrophage infiltration into adipose tissue, and increased hepatic triglyceride content. Furthermore, insulin resistance, hepatic steatosis, and macrophage accumulation in adipose tissue induced by a high-fat diet were reduced extensively in MCP-1 homozygous KO mice compared with WT animals. Finally, acute expression of a dominant-negative mutant of MCP-1 ameliorated insulin resistance in db/db mice and in WT mice fed a high-fat diet. These findings suggest that an increase in MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, insulin resistance, and hepatic steatosis associated with obesity in mice.