| Co-Investigator(Kenkyū-buntansha) |
HARA Kazuo The University of Tokyo, Faculty of Medicine, Medical staff, 医学部附属病院, 医員
TOBE Kazuyuki The University of Tokyo, Faculty of Medicine, Research associate, 医学部附属病院, 助手 (30251242)
YAMAUCHI Toshimasa The University of Tokyo, Faculty of Medicine, Medical staff, 医学部附属病院, 医員
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| Budget Amount *help |
¥13,300,000 (Direct Cost: ¥13,300,000)
Fiscal Year 2001: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2000: ¥9,000,000 (Direct Cost: ¥9,000,000)
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| Research Abstract |
Our knockout mice studies revealed that PPARgamma was absolutely required for adipocyte differentiation (Mol. Cell. 4:597, 1999), and that IRS-1 and IRS-2 played a crucial role in the upregulation of the PPARgamma expression and adipocyte differentiation (Mol. Cell. Biol. 21:2521, 2001). Thiazolidinediones (TZD) ameliorated insulin resistance by increasing the number of small size adipocytes and decreasing hypertrophic adipocytes (J.Clin.Invest. 101:1354, 1998), which was associated with decreased molecules causing insulin resistance (J.Biol.Chem. 276: 41245, 2001) and also increased insulin senisitizing hormone adiponectin (J.Biol.Chem. 277: 25863, 2002). Insulin sensitizing effect of adiponectin appears to be mediated by an increase in fatty acid oxidation via activation of AMP kinase (Nature Medicine 8:1288, 2002) and PPARα (J.Biol.Chem. 278: 2461, 2003), thereby decreasing TG content (Nature Medicine 7:941, 2001). Unexpectedly, heterozygous CBP knockout mice showed increased insuli
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n sensitivity despite lipodystrophy. Heterozygous CBP knockout mice also showed increased effects of insulin sensitizing hormones such as leptin and adiponectin, and these may explain the phenotypes of heterozygous CBP knockout mice at least in part (Nature Genetics 30:221, 2002).
We identified a SNP (Pro12Ala) of human PPARgamma gene. Subjects with Ala allele decreasing PPARgamma activity were associated with resistance to type 2 diabetes (BBRC. 271:212, 2000). PPARgamma antagonist protected against obesity, insulin resistance and type 2 diabetes of KKA^y mice (J.Clin.Invest. 108:1001, 2001). A genetic variation in the PPARgamma coactivator PGC (PPARgamma coactivator)-1 gene could confer insulin resistance and susceptibility to Type 2 diabetes (Diabetologja. 45:740, 2002). The adiponectin SNP associated with lower plasma adiponectin levels had a higher insulin resistance index and also a significantly increased risk of type 2 diabetes (Diabetes. 51:536,2002).
Finally, we tried to identify the endogenous PPARgamma ligands, because PPARgamma ligands potentially can be involved in insulin sensitivity. Current fractionation studies using HPLC suggest a single peak of activity, indicating one or very few components. The chromatographic behavior of this activity indicates that it is not equivalent to 15-deoxy-12,14-PGJ2. Structural determination will shed light on the biochemical nature of this molecule and open the door to the study of its biosynthetic regulation. Less
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