| Budget Amount *help |
¥2,760,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥360,000)
Fiscal Year 2007: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Research Abstract |
We found that purified HMW adiponectin markedly up-regulated ferritin heavy chain (FHC) via NF-κB activation in skeletal muscle cells. We further investigated the regulations of several NF-κB targeted genes in primary skeletal muscle cells exposed to adiponectin, and demonstrated a 6.8-fold increase in FHC, a 2.0-fold increase in MnSOD and a 7.7-fold increase in inducible NOS at the transcriptional level. These up-regulations were unaffected by incubation with the same concentration of type I collagen or recombinant globular adiponectin, suggesting them to be specific to adiponectin multimer formation. In addition, we further confirmed up-regulation of these genes in skeletal muscles of mice which had been treated with adenovirus expressing recombinant adiponectin. Though it is well known that iNOS indirectly reduces superoxide via NO production and that MnSOD directly scavenges superoxide, the physiological role of FHC is not well known. As FHC inhibits hydroxyl radical generation in
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the fenton reaction, we investigated the effect of FHC overexpression on ROS accumulation. Using the ROS assay, we found that recombinant FHC reduced ROS accumulation, induced by various forms of oxidative stress, i. e. 26%(Fe^<2+>), 20%(TNFα) and 49%(4-hydroxynonenal) in C2C12 myotubes. These observations indicate that FHC exerts cytoprotective effects by reducing the ROS accumulation induced by various oxidative stresses. As increased oxidative stress involvement in insulin resistance has been suggested, we investigated the effects of FHC overexpression on the H2O2 induced insulin resistance observed in C2C12 myotubes and 3T3-L1 adipocytes. Interestingly, in the presence of Fe^2+, FHC overexpression greatly improved insulin stimulated IRS-1 phosphorylation or glucose uptake, which was blunted by H2O2 incubation. These results indicate up-regulations of NF-κB targeted genes by adiponectin to be a novel cellular mechanism for reducing both oxidative stress and insulin resistance in skeletal muscle cells. Less
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