Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
J Atheroscler Thromb. 2010 Mar 31;17(3):219-28. doi: 10.5551/jat.3368. Epub 2010 Feb 24.
Adipose tissue inflammation induced by macrophage infiltration through the MCP-1/CCR2 pathway is considered to play a pivotal role in the development of visceral obesity and insulin resistance. In the present study, therefore, we examined whether pharmacological inhibition of CCR2 is effective against the development of diet-induced metabolic disorders.
C57BL/6 mice were fed a high fat and sucrose diet with or without propagermanium (CCR2 inhibitor, 5 or 50 mg/kg BW/day) for 12 weeks from 6 weeks of age. Then we analyzed lipid and glucose metabolism and tissue inflammation in the liver and adipose tissues along with serum markers in those mice.
Propagermanium treatment slightly decreased body weight gain and visceral fat accumulation in diet-induced obese (DIO) mice. Further, propagermanium suppressed macrophage accumulation and shifted adipose tissue macrophage polarization from the pro-inflammatory (M1) state to anti-inflammatory (M2) state in DIO mice. Expressions of TNF-alpha and MCP-1 mRNA in adipose tissue were reduced by propagermanium treatment, indicating that propagermanim suppressed inflammation in adipose tissue. Propagermanium treatment also ameliorated glucose tolerance, insulin sensitivity, and decreased hepatic triglyceride in DIO mice. Thus, propagermanium improved diet-induced obesity and related metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing inflammation in adipose tissue. Our data indicate that inhibition of CCR2 could improve diet-induced metabolic disorders, and that propagermanium may be a beneficial drug for the treatment of metabolic syndrome.
通过单核细胞趋化蛋白 1/CC 趋化因子受体 2（MCP-1/CCR2）通路诱导的脂肪组织炎症被认为在内脏型肥胖和胰岛素抵抗的发展中起关键作用。因此，本研究旨在探讨 CCR2 药理学抑制是否对饮食诱导的代谢紊乱的发展有效。
6 周龄的 C57BL/6 小鼠用高脂肪和高蔗糖饮食喂养 12 周，同时给予或不给予普拉克索（CCR2 抑制剂，5 或 50mg/kgBW/天）。然后分析这些小鼠的脂质和葡萄糖代谢以及肝脏和脂肪组织的组织炎症，并检测血清标志物。
普拉克索治疗可轻微减少饮食诱导肥胖（DIO）小鼠的体重增加和内脏脂肪堆积。此外，普拉克索抑制了 DIO 小鼠脂肪组织中巨噬细胞的积聚，并将脂肪组织巨噬细胞的极化从促炎（M1）状态转变为抗炎（M2）状态。普拉克索治疗还改善了 DIO 小鼠的葡萄糖耐量、胰岛素敏感性，并降低了肝甘油三酯。因此，普拉克索通过抑制脂肪组织炎症改善了饮食诱导的肥胖和相关代谢紊乱，如胰岛素抵抗和肝脂肪变性。这些数据表明，抑制 CCR2 可以改善饮食诱导的代谢紊乱，普拉克索可能是治疗代谢综合征的有益药物。
