1998 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)	植木浩二郎東京大学, 医学部・附属病院, 医員鏑木康志東京大学, 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)
Keywords	チアゾリジン誘導体 / PPARファミリー / PPARγのリガンド / 脂質代謝 / インスリン抵抗性
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BRL-49,653とは対照的に肝臓においてZuckerfattyラットで低下していたパルミチン酸からのCO_2やケトン体産生能が回復することを見出した。また、肝臓での脂質産生や中性脂肪の蓄積の抑制という点でKRP-297は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PPARα、PPARγの活性化能のED_<50>はそれぞれ1.0μmol/L、0.8μmol/Lであった。また、PPARα、PPARγへの結合の解難定数はそれぞれ228nmol/L、326nmol/Lであった。KRP-297は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 etal.,Diabetes47:1841-1847,1998)

Research Products

(12 results)

All Other

All Publications (12 results)

[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)
[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)
[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)
[Publications] Tobe.K.,et al: "Csk enhances insulin-stimulated dephosphorylation of focal adhesion proteins." Mol.Cell.Biol.16. 4765-4772 (1996)
[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] 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)
[Publications] Yamauchi,T.,et al: "Tyrosine phosphorylation of EGF receptor induced by growth hormone via JAK2 kinase." Nature. 390. 91-96 (1997)
[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)
[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 insulin receptor substrate-1,-2,and -3,their association with p85 phosphatidylinositol 3-kinase(P13-kinase),and concomitantly P13-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-Acticvated Receptor-α(PRAR-α)and PPARγ Effect of PPAR-α Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats" Diabetes. 47. 1841-1847 (1998)
[Publications] Terauchi,Y.,et al: "Increased insulin sensityvity and hypoglycaemia in mice lacking the p85 α subunit of phosphoinositide 3-kinase" Nature Genetics. 21. 230-235 (1999)

1998 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] Tamemoto,H.,and Kadowaki,T.,et al: "Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1." Nature. 372. 182-186 (1994)

[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)

[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)

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

[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] 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)

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

[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)

[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] Murakami,K.,et al: "A Novel Insulin sensitizer Acts as a Coligand for Peroxisome Proliferator-Acticvated Receptor-α(PRAR-α)and PPARγ Effect of PPAR-α Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats" Diabetes. 47. 1841-1847 (1998)

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

戸辺一之東京大学, 医学部・附属病院, 助手 (30251242)