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The study for molecular mechanisms of obesity, insulin resistance and atherosclerosis in the PPAR gamma deficient mice

Research Project

Project/Area Number 12470225
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionThe University of Tokyo

Principal Investigator

KADOWAKI Takashi  University of Tokyo, Faculty of Medicin, Associate Professor, 医学部附属病院, 助教授 (30185889)

Co-Investigator(Kenkyū-buntansha) ETO Kazuhiro  University of Tokyo, Faculty of Medicin, Medical staff, 医学部附属病院, 医員
TERAUCHI Yasuo  University of Tokyo, Faculty of Medicin, research associate, 医学部附属病院, 助手
TOBE Kazuyuki  University of Tokyo, Faculty of Medicin research associate, 医学部附属病院, 助手 (30251242)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 2001: ¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 2000: ¥9,100,000 (Direct Cost: ¥9,100,000)
KeywordsHeterozygous PPARγ deficient mice / High-fat diet / Obesity / Insulin resistance / DNA chip / Adiponectin / PPARγ antagonist / Pro12Ala polymorphism / レプチン / PPARγアンタゴニスト(HX531) / 組織内中性脂肪含量 / floxマウス / Creトランスジェニックマウス / Retinoid X受容体アンタゴニスト / DNAチップ
Research Abstract

1. Focusing on the fact that heterozygous PPARgamma deficient mice were protected from the development of obesity and insulin resistance under a high-fat diet, we compared the differences of the gene expression in white adipose tissues between PPARgamma deficient mice and wild-type mice under a high-fat diet by using DNA chip. Adiponectin as well as leptin expression was higher in the PPARgamma deficient mice than in the wild-type mice. These data suggested that adiponectin may be an insulin-sensitizing hormone secreted by adipose tissue. In fact, administration of adiponectin increases fatty acid combustion in muscle, thereby ameliorating insulin resistance in obese mice. These observations indicate that the replenishment of adiponectin might provide a novel treatment modality for insulin resistance and type 2 diabetes.
2. PPARgamma is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). We identified a synthetic RXR antagonist, HX531 … More and investigated whether functional, antagonism toward PPARgamma/RXR could be used to treat obesity and type 2 diabetes. Administration of the RXR antagonist HX531 decreases TG content in white adipose tissue, skeletal muscle, and the liver due to increased leptin effects and increased fatty acid combustion and energy dissipation, thereby ameliorating obesity and insulin resistance. Our data suggest that appropriate functional antagonism of PPARgamma/RXR may be a logical approach to protect against obesity and related diseases such as type 2 diabetes.
3. A Pro12Ala polymorphism has been detected in the human PPARgamma2 gene. Since this amino acid substitution causes a reduction in the transcriptional activity of PPARgamma, this polymorphism may be associated with increased insulin sensitivity and decreased risk of type 2 diabetes. To investigate this hypothesis, we performed a case-control study of the Pro12Ala PPARgamma2 polymorphism in Japanese diabetic and non-diabetic subjects. The frequency of Ala12 was significantly lower in the diabetic group than in the control group. In an overweight or obese group, subjects with Ala12 were more insulin sensitive than those without Ala12. These results suggest that the PPARgamma is a thrifty gene and that the Pro12Ala PPARgamma2 polymorphism protects against type 2 diabetes in the Japanese population.
4. We investigated the role of PPARgamma in the development of atherosclerosis using heterozygous PPARgamma deficient (PPARγ+/-) mice. When we placed a cuff around the femoral artery to induce inflammation of the adventitia and subsequent neointimal formation, the PPARgamma+/- mice showed 2 fold more neointimal formation than the wild-type mice 2 weeks after cuff placement. Moreover, endothelium-dependent vascular relaxation was significantly impaired in the PPARγ+/- mice compared with the wild-type mice and the expression of endothelial nitric oxide synthase (eNOS) was significantly lower in the PPARgamma+/- mice than in the wild-type mice. These data suggested that PPAR amma plays a crucial role in the regulation of vascular endothelial function and the protection from inflammation induced neointimal formation. Less

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (39 results)

All Other

All Publications (39 results)

  • [Publications] Yamauchi T. et al.: "Globular adiponectin protected ob/ob mice from diabetes and apoE deficient mice from atherosclerosis"J. Biol. Chem.. 278. 2461-2468 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamauchi T. et al.: "Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase"Nature Medicine. 8. 1288-1295 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kubota N. et al.: "Disruption of adiponectin causes insulin resistance and neointimal formation"J. Biol. Chem.. 277. 25863-25866 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kadowaki T. et al.: "The role of PPARγ in high-fat diet-induced obesity and insulin resistance"J. Diabetes Complications. 16. 41-45 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamauchi T. et al.: "The mechanisms by which both heterozygous PPARγ deficiency and PPARγ agonist improve insulin resistance"J. Biol. Chem.. 51. 1247-1255 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamauchi T. et al.: "Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes"J. Clin. Invest.. 108. 1001-1013 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamauchi T. et al.: "The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity"Nature Medicine. 7. 941-946 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mori, H. et al.: "The Pro12→Ala substitution in PPARγ is associated with resistance to development of diabetes in the general population : possible involvement in impairment of insulin secretion"Diabetes. 50. 891-894 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hara K.et al.: "The role of PPARγ as a thrifty gene in both in mice and humans"Brit. J. Nutr.. 84. 235-239 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Murakami K, et al.: "Fatty Acyl-CoA thioesters inhibit recruitment of steroid receptor co-activator 1 to alpha and gamma isoforms of peroxisome-proliferator-activated receptors by competing with agonists"Biochem. J.. 353. 231-238 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kadowaki T, et al.: "Insights into insulin resistance and type 2 diabetes from knockout mouse models"J. Clin. Invest.. 106. 459-465 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hara K, et al.: "The Pro12Ala polymorphism in PPARγ2 may confer resistance to type 2 diabetes"Biochem. Biophys. Res. Commun.. 271. 212-216 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamauchi, T., et al.: "Globular adiponection protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis"J. Biol. Chem.. 278. 2461-2468 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Suzawa, M., et al.: "Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade"Nature Cell Biology. 5. 224-230 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamauchi, T, et al.: "Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase"Nature Medicine. 8. 1288-1295 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kubota, N., et al.: "Disruption of adiponectin causes insulin resistance and neointimal formation"J. Biol. Chem.. 277. 25863-25866 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamauchi T., et al.: "Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice signaling"Nature Genetics. 30. 221-226 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamauchi, T., et al.: "The mechanisms by which both heterozygous PPARγ deficiency and PPARγ agonist improve insulin resistance"J. Biol. Chem.. 276. 41245-41254 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamauchi, T., et al.: "Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes"J. Clin. Invest.. 108. 1001-1013 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamauchi, T., et al.: "Replenishment of the fat-derived hormone adiponectin reverses insulin resistance in lipoatrophic diabetes and type 2 diabetes"Nature Medicine. 7. 941-946 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mori, H., et al.: "The Prol2→Ala substitution in PPARγ is associated with resistance to development of diabetes in the general population : possible involvement in impairment of insulin secretion in individuals with type 2 diabetes"Diabetes. 50. 891-894 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hara, K., et al.: "The role of PPARγ as a thrifty gene in both in mice and humans"Brit. J. Nutr.. 84. 235-239 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Murakami, K.: "Fatty Acyl-CoA thioesters inhibit recruitment of steroid receptor co-activator 1 to alpha and gamma isoforms of peroxisome-proliferator-activated receptors by competing with agonists"Biochem. J.. 353. 231-238 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kadowaki, T., et al.: "Insights into insulin resistance and type 2 diabetes from knockout mouse models"J.Clin.Invest.. 106. 459-465 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hara, K., et al.: "The Pro12Ala polymorphism in PPARg2 may confer resistance to type 2 diabetes"Biochem. Biophys. Res. Commun.. 271. 212-216 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Okuno, A., et al.: "Trogliazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats"J Clin Invest. 101. 1354-1361 (1998)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kubota, N., et al.: "PPARγ mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance"Mol.Cell. 4. 597-609 (1999)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hara, K., et al.: "The role of PPARγ as a thrifty gene in both in mice and humans"Brit.J.Nutr.. 84. 235-239 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamauchi, T., et al.: "The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity"Nature Medicine. 7. 941-946 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamauchi, T., et al.: "The central role of PPARγ in the regulation of insulin sensitivity"J.Clin.Invest.. 108. 1001-1013 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamauchi, T., et al.: "The mechanisms by which both heterozygous PPARr deficiency and PPARγ agonist improve insulin resistance"J.Biol.Bhem.. 276. 41245-41254 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okada,T., et al.: "Variants of neurogenis 3 gene are not asoociated with type 2 diabetes in Japanese subjects."Diabetologia. 44. 241-244 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kato,H, et al.: "Mechanism of amelioration of insulin resistance by β-3-adrenoceptor agonist AJ-9677 in KK-Ay/Ta obese diabetic mice."Diabetes,. 50. 113-122 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hara,K., et al.: "The role of PPARγ as a thrifty gene in both in mice and humans."Brit.J.Nutr.. 84. 235-239 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Murakami,K., et al.: "Fatty Acyl-CoA thioesters are antagonists for α and γisoforms of peroxisome proliferators-activated receptors."Biochem.J.. 353. 1-10 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kubota,N., et al.: "Disruption of insulin receptor substrate-2 causes type 2 diabetes due to liver insulin resistance and lack of compensatory β-cell hyperplasia."Diabetes. 49. 1880-1889 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kadowaki,T., et al.: "Molecular pathogenesis of type 2 diabetes and obesity in knockout mice models."J.Clin.Invest.. 106. 459-465 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hara,K., et al.: "A Pro12Ala polymorphism in PPARγ2 may confer resistance to type II diabetes."Biochem.Biophys.Res.Commun.. 271. 212-216 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Terauchi,Y., et al.: "Insulin effect during embryogenesis determines fetal growth.: a possible molocular link between birth weight and susceptibility to type 2 diabetes."Diabetes. 40. 82-86 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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