Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Diabetologia. 2012 Dec;55(12):3350-8. doi: 10.1007/s00125-012-2710-2. Epub 2012 Sep 16.
AIMS/HYPOTHESIS: Monocyte chemoattractant protein-1 (MCP-1)/chemokine (C-C motif) ligand (CCL) 2 (CCL2) secreted from white adipose tissue (WAT) in obesity has been reported to contribute to tissue macrophage accumulation and insulin resistance by inducing a chronic inflammatory state. MCP-1 has been shown to be elevated in the fatty liver of lipoatrophic A-ZIP-transgenic (A-ZIP-Tg) mice. Treatment of these mice with the CC chemokine receptor (CCR) 2 antagonist has been shown to ameliorate the hyperglycaemia, hyperinsulinaemia and hepatomegaly, in conjunction with reducing liver inflammation. However, since CCR2 antagonists can block not only MCP-1 but also MCP-2 (CCL8) and MCP-3 (CCL7), it remains unclear whether MCP-1 secreted from the liver could contribute to hyperglycaemia, hyperinsulinaemia and hepatomegaly in conjunction with liver inflammation, as well as to the M1 and M2 states of macrophage polarisation.
To address these issues, we analysed the effects of targeted disruption of MCP-1 in A-ZIP-Tg mice.
MCP-1 deficiency alone or per se resulted in a significant amelioration of insulin resistance in A-ZIP-Tg mice, which was associated with a suppression of extracellular signal-regulated protein kinase (ERK)-1/2 and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation in liver. Although MCP-1 deficiency did not reduce the expression of macrophage markers, it increased the expression of the genes encoding M2 macrophage markers such as Arg1 and Chi3l3, as well as significantly reducing the triacylglycerol content of livers from A-ZIP-Tg mice. CONCLUSIONS/ INTERPRETATION: Our data clearly indicated that MCP-1 deficiency improved insulin resistance and hepatic steatosis in A-ZIP-Tg mice and was associated with switching macrophage polarisation and suppressing ERK-1/2 and p38MAPK phosphorylation.
目的/假设：肥胖症患者的白色脂肪组织（WAT）分泌的单核细胞趋化蛋白-1（MCP-1）/趋化因子（C-C 基序）配体（CCL）2（CCL2）已被报道通过诱导慢性炎症状态来促进组织巨噬细胞积累和胰岛素抵抗。已经表明 MCP-1 在脂肪营养不良 A-ZIP-转基因（A-ZIP-Tg）小鼠的脂肪肝中升高。用 CC 趋化因子受体（CCR）2 拮抗剂治疗这些小鼠已被证明可以改善高血糖症、高胰岛素血症和肝肿大，同时减少肝脏炎症。然而，由于 CCR2 拮抗剂不仅可以阻断 MCP-1，还可以阻断 MCP-2（CCL8）和 MCP-3（CCL7），因此仍不清楚肝脏分泌的 MCP-1 是否会导致与肝脏炎症以及巨噬细胞极化的 M1 和 M2 状态相关的高血糖症、高胰岛素血症和肝肿大，以及是否会导致高血糖症、高胰岛素血症和肝肿大。 MCP-1 缺乏本身或单独导致 A-ZIP-Tg 小鼠胰岛素抵抗的显著改善，这与肝脏中细胞外信号调节蛋白激酶（ERK）-1/2 和 p38 有丝分裂原激活蛋白激酶（p38MAPK）磷酸化的抑制有关。尽管 MCP-1 缺乏不会降低巨噬细胞标志物的表达，但它会增加 M2 巨噬细胞标志物（如 Arg1 和 Chi3l3）的基因表达，并显著降低 A-ZIP-Tg 小鼠肝脏中的三酰甘油含量。结论/解释：我们的数据清楚地表明，MCP-1 缺乏改善了 A-ZIP-Tg 小鼠的胰岛素抵抗和肝脂肪变性，并与巨噬细胞极化的转变和 ERK-1/2 和 p38MAPK 磷酸化的抑制有关。
