The molecular mechanism of life style-related disease-the role of RhoGTPases in adipose tissue

生活方式相关疾病的分子机制——RhoGTPase在脂肪组织中的作用

• 批准号: 18590987
• 负责人: KOMURO Ryutaro
• 金额: $ 2.57万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590987/
• 关键词: white adipose tissue; mature adinoc; RhoA; inflammation; insulin resistance; adiponectin; Rho-kinase; プロモーター活性; アディポネクチン多量体; 脂肪組織; 脂肪細胞; 肥満

1. RhoA activityin white adipose tissue (WAT): WAT of C57BL/6J mice showed exhemely high activity of RhoGPPases (RhoA, Rac1, and Cdc42) as compared to other examined tissues, and RhoA activity alone was regulated by feeding condition (fast/refed). Such regulation of RhoA activity seen in WAT of wild type mice was disrupted in WAT of db/db mice, and it was consistenty high. These results suggested the crucial association of active RhoA with the development of insulin resistance in WAT.2. RhoA activity in mature adipocytes: RhoA activity seen in preadipocytes was markedly reduced in the early differentiation stage into mature adipocytes The simple maintenance of culture of adipocytes for a long term increased RhoA activity again accompanied by the decreased glucose uptake. TNFα also unregulated RhoA activity in mature adipocytes. The increased production of proinflammatory cytokines mRNAs (PAI-1 and MCP-1) and the activation of inf]ammatory signaling casecades (p38MAPK, JNK, NFκB), both of which was induced by TNFα , was partially suppressed by Y-27632, an inhibitor of ROCK, an important RhoA effector. We observed the simmilar results when we performed the investigations by using fesudil, an alternative ROCK inhibitor. Y-27632 inhibited the suppression of Ghut4 mRNA expression and decreased glucose uptake which were induced byTNFα . These results suggested that high RhoA activity in adipocytes was much involved in inflammation associated with insulin resistance.3. Effect of RhoA activity on adiponectin production: Y-27632 unregulated the mRNAs expression of adiponectin and PPARγ in mature adipocytes. Simultaneonsly, it increased the amount of adiponectin protein, especially high molecular weight type of adiponectin, in the conditioned medium them 3T3-L1 adipocytes.

1.白色脂肪组织（WAT）中的RhoA活性：与其他检查的组织相比，C57 BL/6 J小鼠的WAT显示出非常高的RhoGPPases（RhoA、Rac 1和Cdc 42）活性，并且RhoA活性单独受进食条件（禁食/再进食）调节。在野生型小鼠WAT中观察到的RhoA活性的这种调节在db/db小鼠的WAT中被破坏，并且它是一致的高。这些结果表明，在瓦特的胰岛素抵抗的发展与活性RhoA的关键协会。成熟脂肪细胞中的RhoA活性：在前脂肪细胞中观察到的RhoA活性在分化为成熟脂肪细胞的早期阶段显著降低。脂肪细胞的简单培养长期维持再次增加RhoA活性，伴随着葡萄糖摄取的降低。TNFα也不调节成熟脂肪细胞中的RhoA活性。ROCK抑制剂Y-27632可部分抑制TNFα诱导的促炎性细胞因子派-1和MCP-1的产生和炎症信号通路p38 MAPK、JNK、NFκB的激活。当我们使用非舒地尔（一种替代ROCK抑制剂）进行研究时，我们观察到了类似的结果。Y-27632可抑制TNF α诱导的Ghut 4 mRNA表达抑制和葡萄糖摄取减少。这些结果提示，脂肪细胞中RhoA的高活性与胰岛素抵抗相关的炎症反应密切相关. RhoA活性对脂联素产生的影响：Y-27632不调节成熟脂肪细胞中脂联素和PPARγ的mRNA表达。同时，增加3 T3-L1脂肪细胞条件培养液中脂联素蛋白的含量，尤其是高分子量脂联素的含量。

项目成果

「研究成果報告書概要(和文)」より

摘自《研究结果报告摘要（日文）》

• 发表时间: 2005
• 作者: Kawauchi;et. al.;Nishimura et al.;Dezawa et al.;Yoshizawa et al.;星野 幹雄;星野 幹雄
• 通讯作者: 星野 幹雄