1999 Fiscal Year Annual Research Report

PPARγの内因性リガンドの精製と同定

Research Project

Project/Area Number	10877173
Research Institution	The University of Tokyo
Principal Investigator	戸辺一之東京大学, 医学部・附属病院, 助手 (30251242)
Co-Investigator(Kenkyū-buntansha)	鏑木康志東京大学, 医学部・附属病院, 医員山内敏正東京大学, 医学部・附属病院, 医員門脇孝東京大学, 医学部・附属病院, 講師 (30185889) 植木浩二郎東京大学, 医学部・附属病院, 医員
Keywords	インスリン受容体 / インスリン受容体基質 / IRS-1 / IRS-2 / IRS-3 / インスリン作用 / インスリン抵抗性 / 発生工学
Research Abstract	チアゾリジン誘導体は脂肪細胞に発現しているPPARγに働きかけ脂肪細胞への分化を亢進し、in vivoでインスリン抵抗性を改善する。新たなチアゾリジン誘導体であるKRP-297をZucker fattyラットに投与すると肝臓での脂質産生や中性脂肪の蓄積の抑制という点でBRL-49,653より効果的であった。次にKRP-297のPPARファミリーの活性化能を検討するとこれまでのチアゾリジン誘導体とは異なりPPARαに結合しかつPPARαを活性化することが明らかとなった。さらにKRP-297は肝でのacyl-CoA oxidaseの発現及び活性をそれぞれ1.5倍、1.8倍に上昇させた。KRP-297のPPARγの活性化作用はBRL-49,653に比べて弱いが、全身でのインスリン抵抗性改善作用はBRL-49,653よりも良好である。このことはKPR297のPPARαの活性化作用が存在し肝臓での脂質代謝改善作用などを介して全身でのインスリン抵抗性改善作用に関与しているものと思われた(Murakami et al.,Diabetes47:1841-1847,1998)さらに、我々は、PPARγの生体内の役割を明らかにするためにPPARγの欠損マウスを作製し、高脂肪食下では、PPARγヘテロの欠損マウスは野生型に比べ肥満になりにくくインスリン抵抗性の増悪は軽度であった(Kubota:Mol.Cell,4:597-609,1999)。

Research Products

(12 results)

All Other

All Publications (12 results)

[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)
[Publications] Kubota,N. et al.: "PPARγ mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance"Mol. Cell. 4. 597-609 (1999)
[Publications] Ueki,K. et al.: "Potential role of protein kinase B in insulin-induced glucose transport, glycogen synthesis, and protein synthesis"J. Biol. Chem.. 273. 5315-5322 (1998)
[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)
[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 kinase"J. Biol. Chem.. 273. 15719-15726 (1998)
[Publications] Murakami,K. et al.: "A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-α(PPAR-α) and PPAR-γ. Effect of PPAR-α activation on abnormal lipid metabolism in liver of zucker fatty rats"Diabetes. 47. 1847 (1998)
[Publications] Yamauchi,T. et al.: "Tyrosine phosphorylation of EGF receptor induced by growth hormone via JAK2 kinase"Nature. 7. 390 91-390 96 (1997)
[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. 741-750 (1997)
[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 doabetes as a polygenic disease"J. Clin. Invest.. 99. 861-866 (1997)
[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)
[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)
[Publications] Tobe,K. et al.: "Csk enhances insulin-stimulated dephosphorylation of focal adhesion proteins"Mol. Cell. Biol.. 16. 4765-4772 (1996)

1999 Fiscal Year Annual Research Report

PPARγの内因性リガンドの精製と同定

Principal Investigator

戸辺 一之 東京大学, 医学部・附属病院, 助手 (30251242)

Research Products

[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)

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

[Publications] Ueki,K. et al.: "Potential role of protein kinase B in insulin-induced glucose transport, glycogen synthesis, and protein synthesis"J. Biol. Chem.. 273. 5315-5322 (1998)

[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)

[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 kinase"J. Biol. Chem.. 273. 15719-15726 (1998)

[Publications] Murakami,K. et al.: "A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-α(PPAR-α) and PPAR-γ. Effect of PPAR-α activation on abnormal lipid metabolism in liver of zucker fatty rats"Diabetes. 47. 1847 (1998)

[Publications] Yamauchi,T. et al.: "Tyrosine phosphorylation of EGF receptor induced by growth hormone via JAK2 kinase"Nature. 7. 390 91-390 96 (1997)

[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. 741-750 (1997)

[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 doabetes as a polygenic disease"J. Clin. Invest.. 99. 861-866 (1997)

[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)

[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)

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

戸辺一之東京大学, 医学部・附属病院, 助手 (30251242)