Westerbacka Jukka, Cornér Anja, Kolak Maria, Makkonen Janne, Turpeinen Ursula, Hamsten Anders, Fisher Rachel M, Yki-Järvinen Hannele
University of Helsinki, Department of Medicine, Division of Diabetes, Biomedicum, FIN-00029 HUCH, Helsinki, Finland.
Am J Physiol Endocrinol Metab. 2008 May;294(5):E841-5. doi: 10.1152/ajpendo.00653.2006. Epub 2008 Feb 12.
CCL2 (MCP-1, monocyte chemoattractant protein 1) and CCL3 (MIP-1alpha, macrophage inflammatory protein 1alpha) are required for macrophage infiltration in adipose tissue. Insulin increases CCL2 expression in adipose tissue and in serum more in insulin-resistant obese than in insulin-sensitive lean mice, but whether this is true in humans is unknown. We compared basal expression and insulin regulation of CCL2 and CCL3 in adipose tissue and MCP-1 and MIP-1alpha in serum between insulin-resistant and insulin-sensitive human subjects. Subcutaneous adipose tissue biopsies and blood samples were obtained before and at the end of 6 h of in vivo euglycemic hyperinsulinemia (maintained by the insulin clamp technique) in 11 lean insulin-sensitive and 10 obese insulin-resistant women, and before and after a 6-h saline infusion in 8 women. Adipose tissue mRNA concentrations of monocyte/macrophage markers CD68, EMR1, ITGAM, ADAM8, chemokines CCL2 and CCL3, and housekeeping gene ribosomal protein large P0 (RPLP0) were measured by means of real-time PCR at baseline. In addition, mRNA concentrations of CCL2, CCL3, and RPLP0 were measured after insulin infusion. Levels of MCP-1 and MIP-1alpha were determined in serum, and protein concentration of MCP-1 was determined in adipose tissue at baseline and after insulin infusion. Basally, expression of the macrophage markers CD68 and EMR1 were increased in adipose tissue of insulin-resistant subjects. Insulin increased MCP-1 gene and protein expression significantly more in the insulin-resistant than in the insulin-sensitive subjects. Basally expression of CCL2 and CCL3 and expression of macrophage markers CD68 and ITGAM were significantly correlated. In serum, MCP-1 decreased significantly in insulin-sensitive but not insulin-resistant subjects. MIP-1alpha was undetectable in serum. Insulin regulation of CCL2 differs between insulin-sensitive and -resistant subjects in a direction that could exacerbate adipose tissue inflammation.
CCL2（单核细胞趋化蛋白-1，MCP-1）和CCL3（巨噬细胞炎性蛋白-1α，MIP-1α）是脂肪组织中巨噬细胞浸润所必需的。与胰岛素敏感的瘦小鼠相比，胰岛素抵抗的肥胖小鼠脂肪组织和血清中CCL2的表达增加更多，但在人类中是否如此尚不清楚。我们比较了胰岛素抵抗和胰岛素敏感的人类受试者脂肪组织中CCL2和CCL3以及血清中MCP-1和MIP-1α的基础表达和胰岛素调节情况。在11名瘦的胰岛素敏感女性和10名肥胖的胰岛素抵抗女性体内进行6小时正常血糖高胰岛素血症（通过胰岛素钳夹技术维持）之前和结束时，以及8名女性进行6小时生理盐水输注之前和之后，获取皮下脂肪组织活检样本和血样。通过实时PCR在基线时测量脂肪组织中单核细胞/巨噬细胞标志物CD68、EMR1、ITGAM、ADAM8、趋化因子CCL2和CCL3以及管家基因核糖体蛋白大亚基P0（RPLP0）的mRNA浓度。此外，在胰岛素输注后测量CCL2、CCL3和RPLP0的mRNA浓度。在基线时和胰岛素输注后测定血清中MCP-1和MIP-1α的水平，并测定脂肪组织中MCP-1的蛋白浓度。基础状态下，胰岛素抵抗受试者的脂肪组织中巨噬细胞标志物CD68和EMR1的表达增加。胰岛素使胰岛素抵抗受试者的MCP-1基因和蛋白表达显著高于胰岛素敏感受试者。基础状态下CCL2和CCL3的表达与巨噬细胞标志物CD68和ITGAM的表达显著相关。在血清中，胰岛素敏感受试者的MCP-1显著降低，但胰岛素抵抗受试者中未降低。血清中未检测到MIP-1α。胰岛素敏感和抵抗受试者之间CCL2的胰岛素调节存在差异，这种差异可能会加剧脂肪组织炎症。
