2002 Fiscal Year Annual Research Report

CBPによる脂肪細胞分化・肥大化及びインスリン感受性の調節メカニズム

Research Project

Project/Area Number	13877175
Research Institution	The University of Tokyo
Principal Investigator	門脇孝東京大学, 医学部附属病院, 助教授 (30185889)
Co-Investigator(Kenkyū-buntansha)	山内敏正東京大学, 医学部附属病院, 医員戸辺一之東京大学, 医学部附属病院, 助手 (30251242)
Keywords	転写共役因子 / 脂肪細胞 / 分化 / PPAR / 肥満 / 糖尿病 / アディポネクチン / レプチン
Research Abstract	肥満・抗糖尿病の表現型を呈することを報告した。本年度、PPRγを含めた種々の転写因子の共役因子CBP(CREBb inding 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増加は、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)。さらに野生型と異なり、このCBPヘテロ欠損マウスではレプチン欠損によっても肥満は認められず、血糖上昇も部分的であることを見い出した。アディポネクチン発現ob/obマウスでも肥満の改善は認められず、血糖低下も部分的であった。これらのことより、CBPによる体重・糖代謝調節経路にはPPARγ/レプチン/アディポネクチン非依存性経路も存在し、それらの同定は新規の抗肥満・抗糖尿病薬開発につながり重要であることが示唆された(投稿準備中)。

Research Products

(14 results)

All Other

All Publications (14 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)
[Publications] Yamauchi T, et al.: "Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice.signalling"Nature Genetics. 30. 221-226 (2002)
[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)
[Publications] Kubota N, et al.: "Disruption of adiponectin causes insulin resistance and neointimal formation"J.Biol.Chem.. 277. 25863-25866 (2002)
[Publications] Hara, K, et al.: "A genetic variation in the PGC-1 gene may confer insulin resistance and susceptibility to type II diabetes"Diabetologia. 45. 740-743 (2002)
[Publications] Hara K, et al.: "Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population"Diabetes. 51. 536-540 (2002)
[Publications] 山内敏正, 門脇孝: "エネルギー代謝におけるCBP/p300の役割"分子心血管病. 3-6号. (2002)
[Publications] Colombo, C, et al.: "Transplantation of adipose tissue lacking leptin is unable to reverse the metabolic abnormalities associated with lipoatrophy"Diabetes. 51. 2727-2733 (2002)
[Publications] Vasseur, F, et al.: "Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians"Human Molecular Genetics. 11. 2607-2614 (2002)
[Publications] Asakawa M, et al.: "Peroxisome proliferator-activated receptor gamma plays a critical role in inhibition of cardiac hypertrophy in vitro and in vivo"Circulation. (2003)
[Publications] Suzawa, M, et al.: "Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade"Nature Cell Biology published on line on Feb 24. 105. 1240-1246 (2002)
[Publications] Katayama K, et al.: "A novel PPARγ-gene therapy for inflammatory bowel disease (IBD) : therapeutic application of PPARγ to control inflammation"Gastroenterology. (in press). (2003)
[Publications] Katayama K, et al.: "A novel PPARg-gene therapy to control inflammation associated with inflammatorooy bowel disease in a murine model"Gastroenterology. (in press). (2003)
[Publications] 山内敏正, 窪田直人, 寺内康夫, 門脇孝: "遺伝子改変動物"内科. (2002)

2002 Fiscal Year Annual Research Report

CBPによる脂肪細胞分化・肥大化及びインスリン感受性の調節メカニズム

Principal Investigator

門脇 孝 東京大学, 医学部附属病院, 助教授 (30185889)

Research Products

[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.: "Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice.signalling"Nature Genetics. 30. 221-226 (2002)

[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)

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

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

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

[Publications] 山内敏正, 門脇 孝: "エネルギー代謝におけるCBP/p300の役割"分子心血管病. 3-6号. (2002)

[Publications] Colombo, C, et al.: "Transplantation of adipose tissue lacking leptin is unable to reverse the metabolic abnormalities associated with lipoatrophy"Diabetes. 51. 2727-2733 (2002)

[Publications] Asakawa M, et al.: "Peroxisome proliferator-activated receptor gamma plays a critical role in inhibition of cardiac hypertrophy in vitro and in vivo"Circulation. (2003)

[Publications] Suzawa, M, et al.: "Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade"Nature Cell Biology published on line on Feb 24. 105. 1240-1246 (2002)

[Publications] Katayama K, et al.: "A novel PPARγ-gene therapy for inflammatory bowel disease (IBD) : therapeutic application of PPARγ to control inflammation"Gastroenterology. (in press). (2003)

[Publications] Katayama K, et al.: "A novel PPARg-gene therapy to control inflammation associated with inflammatorooy bowel disease in a murine model"Gastroenterology. (in press). (2003)

[Publications] 山内敏正, 窪田直人, 寺内康夫, 門脇 孝: "遺伝子改変動物"内科. (2002)

門脇孝東京大学, 医学部附属病院, 助教授 (30185889)

[Publications] 山内敏正, 門脇孝: "エネルギー代謝におけるCBP/p300の役割"分子心血管病. 3-6号. (2002)

[Publications] 山内敏正, 窪田直人, 寺内康夫, 門脇孝: "遺伝子改変動物"内科. (2002)