Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance
Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance
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DOI：
10.1074/jbc.m601284200
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发表时间：
2006-09-08
影响因子：
4.8
通讯作者：
Kadowaki, Takashi
中科院分区：
文献类型：
--
作者：
Kamei, Nozomu;Tobe, Kazuyuki;Kadowaki, Takashi
脂肪组织表达和单核细胞趋化蛋白-1 （MCP-1）的循环浓度与肥胖呈正相关。为了确定MCP-1过表达在脂肪中的作用，我们利用脂肪细胞P2 （aP2）启动子（aP2-MCP-1小鼠）产生转基因小鼠。免疫化学、流式细胞术和基因表达分析证实，这些小鼠的血浆MCP-1浓度较高，脂肪组织中巨噬细胞积聚增加。转基因小鼠白色脂肪组织中肿瘤坏死因子- α和白细胞介素-6 mRNA水平和血浆非酯化脂肪酸水平均升高。aP2-MCP-1小鼠表现出胰岛素抵抗，提示脂肪组织的炎症变化可能参与了胰岛素抵抗的发展。高胰岛素-正糖钳夹研究证实了aP2-MCP-1小鼠的胰岛素抵抗，表明转基因小鼠比野生型小鼠具有更低的葡萄糖消失率和更高的内源性葡萄糖生成。与此一致的是，胰岛素诱导的Akt磷酸化在P2-MCP-1小鼠的骨骼肌和肝脏中均显著降低。MCP-1预处理使离体骨骼肌胰岛素刺激的葡萄糖摄取钝化，MEK抑制剂U0126可部分恢复，提示循环MCP-1可能有助于aP2MCP-1小鼠的胰岛素抵抗。我们得出结论，MCP-1的旁分泌和内分泌作用可能有助于aP2-MCP-1小鼠胰岛素抵抗的发展。
Adipose tissue expression and circulating concentrations of monocyte chemoattractant protein-1 (MCP-1) correlate positively with adiposity. To ascertain the roles of MCP-1 overexpression in adipose, we generated transgenic mice by utilizing the adipocyte P2 (aP2) promoter (aP2-MCP-1 mice). These mice had higher plasma MCP-1 concentrations and increased macrophage accumulation in adipose tissues, as confirmed by immunochemical, flow cytometric, and gene expression analyses. Tumornecrosis factor-alpha and interleukin-6 mRNA levels in white adipose tissue and plasma non-esterified fatty acid levels were increased in transgenic mice. aP2-MCP-1 mice showed insulin resistance, suggesting that inflammatory changes in adipose tissues may be involved in the development of insulin resistance. Insulin resistance in aP2-MCP-1 mice was confirmed by hyperinsulinemic euglycemic clamp studies showing that transgenic mice had lower rates of glucose disappearance and higher endogenous glucose production than wild-type mice. Consistent with this, insulin-induced phosphorylations of Akt were significantly decreased in both skeletal muscles and livers of a P2-MCP-1 mice. MCP-1 pretreatment of isolated skeletal muscle blunted insulin-stimulated glucose uptake, which was partially restored by treatment with the MEK inhibitor U0126, suggesting that circulating MCP-1 may contribute to insulin resistance in aP2MCP-1 mice. We concluded that both paracrine and endocrine effects of MCP-1 may contribute to the development of insulin resistance in aP2-MCP-1 mice.