C-C chemokine receptor 2 inhibitor improves diet-induced development of insulin resistance and hepatic steatosis in mice.
C-C chemokine receptor 2 inhibitor improves diet-induced development of insulin resistance and hepatic steatosis in mice.
复制标题
DOI：
10.5551/jat.3368
复制
发表时间：
2010-03
影响因子：
4.4
通讯作者：
Yukinori Tamura;M. Sugimoto;T. Murayama;M. Minami;Yuki Nishikaze;H. Ariyasu;T. Akamizu;T. Kita;M. Yokode;H. Arai
中科院分区：
文献类型：
--
作者：
Yukinori Tamura;M. Sugimoto;T. Murayama;M. Minami;Yuki Nishikaze;H. Ariyasu;T. Akamizu;T. Kita;M. Yokode;H. Arai
目的巨噬细胞通过MCP-1/CCR 2途径浸润脂肪组织，引起脂肪组织炎症反应，在内脏型肥胖和胰岛素抵抗的发生发展中起重要作用。因此，在本研究中，我们研究了CCR 2的药理学抑制是否对饮食诱导的代谢紊乱的发展有效。方法C57 BL/6小鼠从6周龄起连续12周喂饲含或不含丙帕锗（5或50 mg/kg BW/d）的高脂和蔗糖饲料。然后我们分析了这些小鼠的脂质和葡萄糖代谢以及肝脏和脂肪组织中的组织炎症沿着血清标志物。结果与结论锗治疗轻微降低饮食诱导肥胖（DIO）小鼠的体重增加和内脏脂肪堆积。此外，丙帕锗抑制巨噬细胞积聚，并将DIO小鼠中的脂肪组织巨噬细胞极化从促炎（M1）状态转变为抗炎（M2）状态。脂肪组织中TNF-α和MCP-1 mRNA的表达被丙帕锗处理降低，表明丙帕锗抑制脂肪组织中的炎症。锗治疗还改善了DIO小鼠的葡萄糖耐量、胰岛素敏感性，并降低了肝脏甘油三酯。因此，丙帕锗通过抑制脂肪组织中的炎症改善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。我们的数据表明，抑制CCR 2可以改善饮食诱导的代谢紊乱，丙帕锗可能是治疗代谢综合征的有益药物。
AIM 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. METHODS 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. RESULTS AND CONCLUSION 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.