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Dissection of the Mechanism of Obesity-induced Insulin Resistance

Research Project

Project/Area Number 09557077
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 内分泌・代謝学
Research InstitutionUniversity of Tokyo

Principal Investigator

TOBE Kazuyuki  Faculty of Medicine, University of Tokyo, Assistant, 医学部・附属病院, 助手 (30251242)

Co-Investigator(Kenkyū-buntansha) KABURAGI Yasushi  Faculty of Medicine, University of Tokyo, Medical Staff, 医学部・附属病院, 医員
TAMEMOTO Hiroyuki  Faculty of Medicine, University of Tokyo, Medical Staff, 医学部・附属病院, 医員
KADOWAKI Takashi  Faculty of Medicine, University of Tokyo, Lecturer, 医学部・附属病院, 講師 (30185889)
UEKI Kohjiroh  Faculty of Medicine, University of Tokyo, Medical Staff
植木 浩二郎  東京大学, 医学部・附属病院, 医員
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥10,900,000 (Direct Cost: ¥10,900,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1998: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1997: ¥5,000,000 (Direct Cost: ¥5,000,000)
Keywordsobesity / thiazolidinedione derivatives / insulin resistance / adipocyte / PPARγ / leptin / 抗肥満遺伝子 / 抗糖尿病遺伝子 / チアゾリジン誘導体 / トログリタゾン / 肥満
Research Abstract

Troglitazone (CS-045) is one of the thiazolidinediones that activate the peroxisome proliferator-activated receptor γ (PPARγ), which is expressed primarily in adipose tissues. To eluciadate the mechanism by which troglitazone relieves insulin resistance in vivo, we studied its effects on the white adipose tissues of an obese animal model (obese Zucker rat). Administration of troglitazone for 15 d normalized mild hyperglycemia and marked hyperinsulinemia in these rats. Plasma triglyceride level was decreased by troglitazone in both obese and lean rats. Troglitazone did not change the total weight of white adipose tissues but increased the number of small adipocytes (<2,500μmィイD12ィエD1) approximately fourfold in both retroperitoneal and subcutaneous adipose tissues of obese rats. It also decreased the number of large adipocytes (> 5,000μmィイD12ィエD1) by〜50%. In fact, the percentage of apoptotic nuclei was 〜2.5-fold higher in the troglitazone-treated retroperitoneal white adipose tissue, tha … More n, control. Concomitantly, troglitazone normalized the, expression levels of TNF- α which were elevated by 2-and 1.4-fold in the retroperitoneal and mesenteric white adipose tissues of the obese rats, respectively. Troglitazone also caused a dramatic decrease in the expression levels of leptin, which were increased by 4-10-fold in the white adipose tissues of obese rats. These results suggest that the primary action of troglitazone may be to increase the number of small adipocytes in white adipose tissues, presumably via PPARγ. The increase number of small adipocytes and the decreased number of large adipocytes in white adipose tissues of troglitazone-treated obese rats appear to be an important mechanism by which increased expression levels of TNF- α and higher levels of plasma lipids are normalized, leading to alleviation of insulin resistance(Okuno et al., J. Clin. Invest. 101, 1354-1361, 1998). Furthermore, we have made PPARγ deficient mice. Under high diet PPARγ(+/-) mice have been shown to be protected from obesity and insulin resistance with higher serum levels of leptin compared with those in wild-type mice(Kubota et al, Mol. Cell. 4, 597-609, 1999). suggesting that PPARγ activity promotes increased obesity and insulin resistance under high fat diet. Furthermore, through the search of diabetic patients, the number of the 5ubJects with PPARγ Prol2Ala allele(less activity form of PPARγ2) in diabetic group are less than that in control non-diabetic group(Hara et al, diabetologia in press). Less

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (54 results)

All Other

All Publications (54 results)

  • [Publications] Terauchi, Y. et al: "Increased insulin sensitivity and hypoglycemia in mice lacking p85a subunit of phosphoinositide 3-kinase"Nature Genetics. 21. 230-235 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kubota, N. et al: "PPARr mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance"Mol . Cell,. 4. 597-609 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ueki, k. et al: "potential role of protein kinase B in insulin-induced glucose transport, glucogen synthesis, and protein synthesis"J. Biol, Chem.. 273. 3515-5322 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Okuno, A. et al: "Troglitazone 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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yamauchi, T. et al: "Growth hormone and prolactin stimulate tyrosine phosphorylation of IRS-1, 2,3, their association with p85 PI3-kinase and concomitantly PI3-kinase activation via JAK2 kinae."J.Biol. Chem.. 273. 15719-15726 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 6 Murakami, K. et al: "Novel insulin sensitizer acting as a coligand for PPAR 1 and r"Diabetes. 47. 1841-1847 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yamauchi, T. et al: "Tyrosine phosphorylationof EGF receptor induced by growth hormone via JAK2 kinase"Nature. 390. 91-96 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takahashi, Y. et al: "Roles of insulin receptor substrate-1 and she on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblasts"Endocrinology. 138. 741-750 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Terauchi, Y. et al: "Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and b-cell glucokinase genes:genetic reconstitution of diabetes as a polygenic disease"J. Clin. Invest.. 99. 861-866 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kaburagi, Y. et al: "Role of insulin receptor substate-1 and pp60 in the regulation of insulin-induced glucose transport and GLUT4 translocation in primary adipocytes"J. Biol, Chem.. 272. 25839-25844 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yamauchi, T. et al: "Insulin signaling and insulin actions in the muscles and livers of insulin resistant, insulin receptor substrate 1-deficient mice."Mol. Cell. Biol.. 16. 3074-3084 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tobe, K. et al: "Csk enhances insulin-stimulated dephosphorylation of focal adhesion proteins"Mol. Cell. Biol.. 16. 4765-4772 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Terauchi, Y. et al.: "Increased insulin sensitivity and hypoglycemia in mice lacking p85α subunit of phosphoinositide 3-kinase."Nature Genetics. 21. 230-235 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kubota, N. et al.: "PPARγ mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance."Mol. Cell. 4. 597-609 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ueki, K. et al.: "Potential role of protein kinase B in insu lin-induced glucose transport, glycogen synthesis, and protein synthesis"J. Biol. Chem.. 273. 3515-5322 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Okuno, A. et al.: "Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass obese in Zucker rats."J. Clin. Invest.. 101. 1354-1361 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yamauchi, T., et al.: "Growth hormone and prolactin stimulate tyrosine phosphorylation of IRS-1, 2, 3, their association with p85 PI3-kinase and concomitasntly PI3-kinase activation via JAK2 kinase."J. Biol. Chem.. 273. 15719-15726 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Murakami, K. et al.: "Novel insulin sensitizer acting as a coligand for PPARα and γ."Diabetes. 47. 1841-1847 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yamauchi, T. et al.: "Tyrosine phosphorylation of EGF receptor induced by growth hormone via JAK2 kinase"Nature. 390. 91-96 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takahashi, Y. et al.: "Roles of insulin receptor substrate-1 and shc on insulin-like growth factor I receptor signaling in early passages of culuterd human fibrobalsts."Endocrinology. 138. 741-750 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Terauchi, Y. et al.: "Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and β-cell glucokinase genes : genetic reconstitution of diabetes as a polygenic disease."J. Clin. Invest.. 99. 861-866 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kaburagi, Y. et al.: "Role of insulin receptor substrate-1 and pp60 in the regulation of insulin-induced glucose transport and GLUT4 translocation in primary adipocytes."J. Biol. Chem.. 272. 25839-25844 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yamauchi, T. et al.: "Insulin signaling and insulin actions in the muscles and livers of insulin resistant, insulin receptor substrate 1-deficient mice."Mol. Cell. Biol.. 16. 3074-3084 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tobe, K. et al.: "Csk enhances insulin-stimulated dephosphorylation of focal adhesion proteins"Mol. Cell. Biol.. 16. 4765-4772 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Terauchi,Y.et al.: "Increased insulin sensitivity and hypoglycemia in mice lacking p85α subunit of phosphoinositide 3-kinase"Nature Genetics. 21. 230-235 (1999)

    • Related Report
      1999 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
      1999 Annual Research Report
  • [Publications] Ueki,K.et al.: "Potential role of protein kinase B in insulin-induced glucose transport, glucogen synthesis, and protein synthesis"J.Biol.Chem.. 273. 3515-3522 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Okuno,A.et al.: "Troglitazone 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
      1999 Annual Research Report
  • [Publications] Yamauchi,T.et al.: "Growth hormone and prolactin stimulate tyrosine phosphorylation of IRS-1,2,3,their association with p85 PI3-kinase and concomitantly PI3-kinase activation via JAK2 kinae"J.Biol.Chem.. 273. 15719-15726 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Murakami,K.et al.: "Novel insulin sensitizer acting as a coligand for PPAR α and γ"Diabetes. 47. 1841-1847 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yamauchi,T.et al.: "Tyrosine phosphorylation of EGF receptor induced by growth hormone via JAK2 kinese"Nature. 390. 91-96 (1997)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takahashi,Y.et al.: "Roles of insulin receptor substrate-1 and shc on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblasts"Endocrinology. 138. 741-759 (1997)

    • Related Report
      1999 Annual Research Report
  • [Publications] Terauchi,Y.et al.: "Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and β-cell glucokinase genes: genetic reconstitution of diabetes as a polygenic disease"J.Clin.Invest.. 99. 861-866 (1997)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kaburagi,Y.et al.: "Role of insulin receptor substrate-1 and pp60 in the regulation of insulin-induced glucose transport and GLUT4 translocation in primary adipocytes"J.Biol.Chem.. 272. 25839-25844 (1997)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yamauchi,T.et al.: "Insulin signalling and insulin actions in the muscles and livers of insulin resistant,insulin receptor substrate 1-deficient mice"Mol.Cell.Biol.. 16. 3074-3084 (1996)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tobe,K.et al.: "Csk enhances insulin-stimulated dephosphorylation of focal adhesion proteins"Mol.Cell.Biol.. 16. 4765-4772 (1996)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tamemoto,H.,and Kadowaki,T.,et al: "Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1." Nature. 372. 182-186 (1994)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tobe,K.,et al: "Identification of a 190-kDa protein as a novel substrate for the insulin receptor kinase functionally similar to insulin receptor substrate-1." J.Biol.Chem.270. 5698-5701 (1995)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yamauchi,T.,et al: "Insulin signaling and insulin actions in the muscle and liver of insulin resistant IRS-1 deficient mice." Mol.Cell.Biol.16. 3074-3084 (1996)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tobe,K.,et al: "Csk enhances insulin-stimulated dephosphorylation of focal adhesion proteins." Mol.Cell.Biol.16. 4765-4772 (1996)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kaburagi,Y.,et al: "Role of insulin receptor substrate-1 and pp60 in the regulation of insulin-induced glucose transport and GLUT4 translocation in primary adipocytes." J.Biol.Chem.272. 25839-25844 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Terauchi,Y.,et al: "Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and β-cell glucokinase genes : genetic reconstitution of diabetes as a polygenic disease." J.Clin.Invest.99. 861-866 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yamauchi,T.,et al: "Tyrosine phosphorylation of EGF receptor induced by growth hormone via JAK2 kinase." Nature. 390. 91-96 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ueki,K.,et al: "Protein kinase B (c-Akt) regulates glucose transport,glycogen synthesis and protein synthesis by insulin." J.Biol.Chem.273. 5315-5322 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Okuno,A.,et al: "Troglitazone 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
      1998 Annual Research Report
  • [Publications] Yamauchi,T.,et al: "Growth hormone and prolactin stimulate tyrosine phosphorylation of insulin receptor substrate-1,-2,and -3,their association with p85 phosphatidylinositol 3-kinase(PI3-kinase),and concomitantly PI3-kinase activation via JAK2 kinase." J.Biol.Chem.273. 15719-15726 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Murakami,K.,et al: "A Novel Insulin Sensitizer Acts as a Coligand for Peroxisome Proliferator-Acticvated Receptor -α(PPAR-α)and PPAR_γ Effect of PPAR-α Activation Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats" Diabetes. 47. 1481-1847 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Terauchi,Y.,et al: "Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 α subunit of phosphoinositide 3-kinase" Nature Genetics. 21. 230-235 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tobe,K., et al: "Tyrosine phosphorylation of EGF receptor induced by growth hormone via JAK2 kinase." Nature. (in press). (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tobe,K., et al: "Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats." J.Clin.Invest.(in press).

    • Related Report
      1997 Annual Research Report
  • [Publications] Tobe,K., et al: "Protein kinase B (c-Akt) regulates glucose transport,glycogen synthesis and protein synthesis by insulin." J.Biol.Chem.(in press). (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tobe,K., et al: "Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and b-cell glucokinaze genes:genetic reconstitution of diabetes as a polygenic disease." J.Clin.Invest.99. 861-866 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tobe,K., et al: "Role of insulin receptor substrate-1 and pp60 in the regulation of insulin-induced glucose transport and GLUT4 translocation in primary adipocytes." J.Biol.Chem.272. 25839-25844 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tobe,K, et al: "Csk enhances insulin-stimulated dephosphorylation of focal adhesion proteins." Mol.Cell.Biol.16. 4765-4772 (1996)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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