| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
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.
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