2002 Fiscal Year Annual Research Report

PPARγアンタゴニストによる新規肥満・抗インスリン抵抗性・抗動脈硬化薬の開発

Research Project

Project/Area Number	13557092
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)	寺内康夫東京大学, 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, 助教授 (30185889)
Keywords	肥満 / インスリン抵抗性 / PPARγ / 脂肪細胞 / レプチン / チアゾリジン誘導体 / アディポネクチン
Research Abstract	リガンド応答性の核内受容体型転写因子PPARγ活性のヘテロ欠損による中等度の低下及びアゴニストによる著明な活性化が、高脂肪食負荷下で、両者とも脂肪細胞小型化をもたらし、インスリン抵抗性惹起分子であるTNFαやレジスチンの発現や遊離脂肪酸の血中レベルの低下と、エネルギー消費や脂肪酸燃焼を促進するインスリン感受性ホルモンであるレプチン・アディポネクチンの発現増加を促進することを明らかにした(Nature Medicine 7:941,2001;J. Biol. Chem.276:41245,2001)。この脂肪細胞小型化をもたらす治療法として、PPARγ活性の部分的阻害剤が、新規抗肥満、抗糖尿病薬となりうることを示した(J. Crin. Invest.108:1001,2001)。さらに、PPARγを含めた種々の転写因子の共役因子CBP(CREB binding protein)のヘテロ欠損マウスがPPARγヘテロ欠損マウスに比し、より顕著な抗肥満、抗糖尿病の表現型を呈することを見い出した。本マウスで認められるエネルギー消費とインスリン感受性のe揄チは、レプチン感受性の亢進と、アディポネクチンの増加と相関した。(Nature Genetics 30,221,2002)。このアディポネクチンの抗糖尿病作用機構として急性にはAMPキナーゼを、慢性にはPPARαを活性化し、脂肪酸燃焼などを促進して、組織内中性脂肪含量を低下させて、インスリン抵抗性を改善させていることを見い出した(Nature Medicine 8:1288,2002;J. Biol. Chem.278:2461,2003)。さらにこのアディポネクチン過剰発現がSRAやTNFαの抑制を介して動脈硬化を抑制することを示した(J.Biol.Chem.278:2461,2003)。

Research Products

(22 results)

All Other

All Publications (22 results)

[Publications] Terauchi, Y., et al.: "Impact of genetic background and ablation of IRS-3 on IRS-2 knockout mice"J.Biol.Chem.. (in press). (2003)
[Publications] Tobe, K., et al.: "Cytoskeletal reorganization induced byinsulin : involvement of Grb2/Ash, Ras and phosphatidylinositol 3-kinase signaling"Genes to Cells. 8. 29-40 (2003)
[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)
[Publications] Yamauchi, T., et al.: "Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase"Nat.Med.. 8. 1288-1295 (2002)
[Publications] Kubota, N., et al.: "Disruption of adiponectin causes insulin resistance and neointimal formation"J.Biol.Chem.. 277. 25863-25866 (2002)
[Publications] Imai, Y., et al.: "Resistance to neointimal hyperplasia and fatty streak formation in mice with adrenomedullin overexpression"Arterioscler Thromb Vasc Biol.. 22. 1310-1315 (2002)
[Publications] Kadowaki, T., et al.: "The role of PPARgamma in high-fat diet-induced obesity and insulin resistance"J. Diabetes Complications. 16. 41-45 (2002)
[Publications] Hara, K., et al.: "A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes"Diabetologia. 45. 740-743 (2002)
[Publications] Hara, K., et al.: "Maturity-onset diabetes of the young resulting from a novel mutation in the HNF-4alpha gene"Intern Med.. 41. 848-852 (2002)
[Publications] Eto, K., et al.: "Phosphatidylinositol 3-kinase suppresses glucose-stimulated insulin secretion by affecting post-cytosolic [Ca(2+)] elevation signals"Diabetes. 51. 87-97 (2002)
[Publications] Mori, Y., et al.: "Genome-wide search for type 2 diabetes susceptibility genes in Japanese affected sibpairs. Autosomal scan supplemented with markers for 12 transcription factor genes and adiponectin gene"Diabetes. 51. 1247-1255 (2002)
[Publications] Hara, K., et al.: "Genetic variation in the gene encoding adiponectin is associated with increased risk of type 2 diabetes in the Japanese population"Diabetes. 51. 536-540 (2002)
[Publications] Akune, T., et al.: "Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts"J.Cell Biol.. 159. 147-156 (2002)
[Publications] Shindo, T., et al.: "Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling"Nature Medicine. 8. 856-863 (2002)
[Publications] Hara, K., et al.: "Role of PPARγ as a thrifty gene in high-fat diet-induced adipocyte hypertrophy and insulin resistance"Brit.J.Nutr. 84. 235-239 (2001)
[Publications] Tsuji, Y., et al.: "Distinct subcellular localization and IRS family proteins associating PI3-kinase activity following insulin stimulation and its functional implications in primary mice adipocytes"Diabetes. 50. 1455-1463 (2001)
[Publications] Miki, H., et al.: "Essential role of IRS-1 and IRS-2 in adipocyte differentiation"Mol.Cell.Biol.. 21. 2521-2531 (2001)
[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)
[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)
[Publications] Chen, W.S., et al.: "Growth retardation and increased apoptosis in mice with homozygous disruption of the akt1 gene"Genes Dev.. 15. 2203-2208 (2001)
[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)
[Publications] Tobe, K., et al.: "Increased Expression of SREBP-1 gene in IRS-2(-/-) mice liver"J.Biol.Chem.. 276. 38337-38340 (2001)

2002 Fiscal Year Annual Research Report

PPARγアンタゴニストによる新規肥満・抗インスリン抵抗性・抗動脈硬化薬の開発

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.: "Impact of genetic background and ablation of IRS-3 on IRS-2 knockout mice"J.Biol.Chem.. (in press). (2003)

[Publications] Tobe, K., et al.: "Cytoskeletal reorganization induced byinsulin : involvement of Grb2/Ash, Ras and phosphatidylinositol 3-kinase signaling"Genes to Cells. 8. 29-40 (2003)

[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)

[Publications] Yamauchi, T., et al.: "Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase"Nat.Med.. 8. 1288-1295 (2002)

[Publications] Kubota, N., et al.: "Disruption of adiponectin causes insulin resistance and neointimal formation"J.Biol.Chem.. 277. 25863-25866 (2002)

[Publications] Imai, Y., et al.: "Resistance to neointimal hyperplasia and fatty streak formation in mice with adrenomedullin overexpression"Arterioscler Thromb Vasc Biol.. 22. 1310-1315 (2002)

[Publications] Kadowaki, T., et al.: "The role of PPARgamma in high-fat diet-induced obesity and insulin resistance"J. Diabetes Complications. 16. 41-45 (2002)

[Publications] Hara, K., et al.: "A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes"Diabetologia. 45. 740-743 (2002)

[Publications] Hara, K., et al.: "Maturity-onset diabetes of the young resulting from a novel mutation in the HNF-4alpha gene"Intern Med.. 41. 848-852 (2002)

[Publications] Eto, K., et al.: "Phosphatidylinositol 3-kinase suppresses glucose-stimulated insulin secretion by affecting post-cytosolic [Ca(2+)] elevation signals"Diabetes. 51. 87-97 (2002)

[Publications] Mori, Y., et al.: "Genome-wide search for type 2 diabetes susceptibility genes in Japanese affected sibpairs. Autosomal scan supplemented with markers for 12 transcription factor genes and adiponectin gene"Diabetes. 51. 1247-1255 (2002)

[Publications] Hara, K., et al.: "Genetic variation in the gene encoding adiponectin is associated with increased risk of type 2 diabetes in the Japanese population"Diabetes. 51. 536-540 (2002)

[Publications] Akune, T., et al.: "Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts"J.Cell Biol.. 159. 147-156 (2002)

[Publications] Shindo, T., et al.: "Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling"Nature Medicine. 8. 856-863 (2002)

[Publications] Hara, K., et al.: "Role of PPARγ as a thrifty gene in high-fat diet-induced adipocyte hypertrophy and insulin resistance"Brit.J.Nutr. 84. 235-239 (2001)

[Publications] Tsuji, Y., et al.: "Distinct subcellular localization and IRS family proteins associating PI3-kinase activity following insulin stimulation and its functional implications in primary mice adipocytes"Diabetes. 50. 1455-1463 (2001)

[Publications] Miki, H., et al.: "Essential role of IRS-1 and IRS-2 in adipocyte differentiation"Mol.Cell.Biol.. 21. 2521-2531 (2001)

[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)

[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)

[Publications] Chen, W.S., et al.: "Growth retardation and increased apoptosis in mice with homozygous disruption of the akt1 gene"Genes Dev.. 15. 2203-2208 (2001)

[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)

[Publications] Tobe, K., et al.: "Increased Expression of SREBP-1 gene in IRS-2(-/-) mice liver"J.Biol.Chem.. 276. 38337-38340 (2001)

戸辺一之東京大学, 医学部附属病院, 助手 (30251242)