2000 Fiscal Year Annual Research Report

脂肪細胞由来の多彩な新規生理活性物質の発見と生理学的及び病理学的意義の解明-Common disease発症の分子機構における脂肪細胞中心説の確立-

Research Project

Project/Area Number	12307022
Research Institution	Osaka University
Principal Investigator	松澤佑次大阪大学, 医学系研究科, 教授 (70116101)
Co-Investigator(Kenkyū-buntansha)	中村正大阪大学, 医学系研究科, 助手 (90252668) 山下静也大阪大学, 医学系研究科, 助教授 (60243242) 船橋徹大阪大学, 医学系研究科, 講師 (60243234) 酒井尚彦大阪大学, 医学系研究科, 助手 (80294073) 平岡久豊大阪大学, 医学系研究科, 助手 (00273681)
Keywords	内臓脂肪 / adipocytokine / adiponectin / aquaporin adipose
Research Abstract	我が国の医療費の大きな割合を占める糖尿病、高脂血症、高血圧や動脈硬化性疾患などのcommon disease発症の共通の基盤として、過栄養、運動不足による脂肪組織の過剰蓄積が極めて大きな位置を占めている。私達は肥満により発症する病態は、必ずしも脂肪蓄積の程度と関連するのではなく、腹腔内内臓脂肪の蓄積と密接につながる事実を明らかにし、内臓脂肪型肥満という疾病概念を提唱した。この知見をもとに脂肪細胞とくに内臓脂肪の代謝学的、及び分子生物学的特性を明らかにすることが多彩なcommon disease発症メカニズムの解明に大きく貢献すると考え、脂肪細胞発現遺伝子の同定と解析を行った。その結果単にエネルギー備蓄細胞と考えられてきた脂肪細胞が多彩な生理活性物質を分泌する内分泌細胞であり、その中で従来脂肪細胞との関連が予想もされなかった血管作動性物質が内臓脂肪から多量に分泌され動脈硬化発症の分子機構のひとつであることを見出した。さらに脂肪細胞特異的に発現する新規のコラーゲン様蛋白としてadiponectinを発見し、本分子が動脈硬化に関連する血管細胞現象を強く抑制する作用や抗炎症作用を有することを明らかにした。本研究の目的は栄養状態に応じて活発に増減する特異な細胞である脂肪細胞が巨大な内分泌臓器として多彩な生理活性物質(adipocytokine)の分泌を行い生体防御に貢献しているが、肥満時にその分泌が変化することにより、栄養状態と強く関連するcommon diseaseの発症を制御していること(脂肪細胞中心性仮説)を証明することである。本年度は私達が同定したadiponectinの単球及びマクロファージに対する様々なサイトカイン分泌におよぼす効果、及び内皮細胞機能に対する効果を細胞内シグナル伝達機構の作用点を明らかにし報告した。さらに脂肪細胞分化に関わるPPAR-γがadiponectin発現に及ぼす影響を検討し、その高親和性リガンドであるチアゾリジン系の効果を明らかにした。adiponectinは肥満や2型糖尿病でその血中濃度が低下しているが、本分子とインスリン抵抗性との関連を検討し報告した。現在本分子がインスリン感受性そのものに及ぼす影響を検討している。また本分子の抗動脈硬化作用をin vivoで明らかにするために生体投与実験、ノックアウトマウスの解析が進行中である。他に私達が新規分子として同定した脂肪細胞特異的グリセロール・チャネル分子aquaporin adiposeの発現調節機構や遺伝子変異の解析、differential display法により得た内臓脂肪特異的分泌因子の機能的特性、さらに内臓脂肪症候群との関連の検討を行っている。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Hotta K,Funahashi T,Bodkin NL,Ortmeyer HK,Arita Y,Hansen BC,and Matsuzawa Y: "Circulating concentrations of the adipocyte protein, adiponectin, are decreased in parallel with reduced insulin sensitivity during the progression to type-2 diabetes in rhesus monkeys."Diabetes. (in press). (2001)
[Publications] Weyer C,Funahashi T,Tanaka S,Hotta K,Matsuzawa Y,Pratley RE,Tataranni PA: "Hypoadiponectinemia in obesity and type 2 diabetes : Evidence for a role of insulin resistance and/or hyperinsulinemia."J.Clin.Endocrinol.Metab. (in press). (2001)
[Publications] Nakamura T,Tsubono Y,Takemura K,Funahashi T,Matsuzawa y et al.: "Magnitude of sustained multiple risk factors for ischemic heart disease in Japanese employees"Jpn.Circ.J.. (in press). (2001)
[Publications] Kobayashi H,Nakamura T,Miyaoka K,Nishida M,Funahashi T,Matsuzawa Y et al: "Visceral fat accumulation contributes to insulin resistance, small-sized low-density lipoprotein, and progression of coronary artery disease in middle-aged non-obese Japanese men"Jpn.Circ.J.. (in press). (2001)
[Publications] Ouchi N,Kihara S,Arita Y,Nishida M,Funahashi T,Matsuzawa Y et al.: "Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages."Circulation. 103. 1057-1063 (2001)
[Publications] Nishigori H,Tomura H,Tonooka N,Yamagata K,Matsuzawa Y,Takeda J. et al: "Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects."Proc Natl Acad Sci USA.. 98. 575-580 (2001)
[Publications] Imagawa A,Hanafusa T,Miyagawa J,Matsuzawa Y.: "A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies."N Engl J Med.. 342. 301-307 (2000)
[Publications] Ouchi N,Kihara S,Arita Y,Okamoto Y,Funahashi T,and Matsuzawa Y et al.: "Adiponectin, adipocyte-derived plasma protein, inhibits endothelial NF-kB signaling through cAMP-dependent pathway."Circulation. 102. 1296-1301 (2000)
[Publications] Yamamoto K,Miyagawa J,Waguri M,Hanafuse T,Matsuzawa Y. et al: "Recombinant human betacellulin promotes the neogenesis of beta-cells and ameliorates glucose intolerance in mice with diabetes induced by selective by selective alloxan perfusion."Diabetes. 49. 2021-2027 (2000)
[Publications] Hirano K,Matsuura F,Tsukamoto K,Matsuzawa Y et al: "Decreased expression of a member of the Rho GTPase family, Cdc42Hs, in cells from Tangier disease-the small G protein may play a role in cholesterol efflux."FEBS Lett.. 484. 275-279 (2000)
[Publications] Zhu Q,Yamagata K,Yu L,Tomura H,Hanafusa T,Matsuzawa Y. et al: "Identification of missense mutations in the hepatocyte nuclear factor-3beta gene in Japanese subjects with late-onset Type II diabetes mellitus."Diabetologia.. 43. 1197-1200 (2000)
[Publications] Matsuyama A,Yamashita S,Sakai N,Hirano K,Kihara S,Matsuzawa Y et al: "Identification of a GPI-anchored type HDL-binding protein on human macrophages."Biochem Biophys Res Commun.. 272. 864-871 (2000)
[Publications] Yokota T,Oritani K,Funahashi T,Tenner AJ,Tomiyama Y,Matsuzawa Y et al.: "Adiponectin, a novel member of soluble defense collagens, negatively regulates the growth of myelo-monocytic progenitors and the functions of macrophages."Blood. 96. 1723-1732 (2000)
[Publications] Takahashi1 M,Arita Y,Yamagata K,Funahashi T,and Matsuzawa Y et al.: "Genomic structure and mutations in adipose-specific gene, adiponectin."Int.J.Obes.. 24. 861-868 (2000)
[Publications] Hotta K,Funahashi T,Arita Y,Takahashi M,Matsuzawa Y et al.: "Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients."Arterioscler Thromb Vasc Biol.. 20. 1595-1599 (2000)
[Publications] Okamoto Y,Arita Y,Nishida M,Funahashi T,Matsuzawa Y et al.: "An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls."Horm Metab Res.. 32. 47-50 (2000)

2000 Fiscal Year Annual Research Report

脂肪細胞由来の多彩な新規生理活性物質の発見と生理学的及び病理学的意義の解明-Common disease発症の分子機構における脂肪細胞中心説の確立-

Principal Investigator

松澤 佑次 大阪大学, 医学系研究科, 教授 (70116101)

Research Products

[Publications] Weyer C,Funahashi T,Tanaka S,Hotta K,Matsuzawa Y,Pratley RE,Tataranni PA: "Hypoadiponectinemia in obesity and type 2 diabetes : Evidence for a role of insulin resistance and/or hyperinsulinemia."J.Clin.Endocrinol.Metab. (in press). (2001)

[Publications] Nakamura T,Tsubono Y,Takemura K,Funahashi T,Matsuzawa y et al.: "Magnitude of sustained multiple risk factors for ischemic heart disease in Japanese employees"Jpn.Circ.J.. (in press). (2001)

[Publications] Ouchi N,Kihara S,Arita Y,Nishida M,Funahashi T,Matsuzawa Y et al.: "Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages."Circulation. 103. 1057-1063 (2001)

[Publications] Nishigori H,Tomura H,Tonooka N,Yamagata K,Matsuzawa Y,Takeda J. et al: "Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects."Proc Natl Acad Sci USA.. 98. 575-580 (2001)

[Publications] Imagawa A,Hanafusa T,Miyagawa J,Matsuzawa Y.: "A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies."N Engl J Med.. 342. 301-307 (2000)

[Publications] Ouchi N,Kihara S,Arita Y,Okamoto Y,Funahashi T,and Matsuzawa Y et al.: "Adiponectin, adipocyte-derived plasma protein, inhibits endothelial NF-kB signaling through cAMP-dependent pathway."Circulation. 102. 1296-1301 (2000)

[Publications] Yamamoto K,Miyagawa J,Waguri M,Hanafuse T,Matsuzawa Y. et al: "Recombinant human betacellulin promotes the neogenesis of beta-cells and ameliorates glucose intolerance in mice with diabetes induced by selective by selective alloxan perfusion."Diabetes. 49. 2021-2027 (2000)

[Publications] Hirano K,Matsuura F,Tsukamoto K,Matsuzawa Y et al: "Decreased expression of a member of the Rho GTPase family, Cdc42Hs, in cells from Tangier disease-the small G protein may play a role in cholesterol efflux."FEBS Lett.. 484. 275-279 (2000)

[Publications] Zhu Q,Yamagata K,Yu L,Tomura H,Hanafusa T,Matsuzawa Y. et al: "Identification of missense mutations in the hepatocyte nuclear factor-3beta gene in Japanese subjects with late-onset Type II diabetes mellitus."Diabetologia.. 43. 1197-1200 (2000)

[Publications] Matsuyama A,Yamashita S,Sakai N,Hirano K,Kihara S,Matsuzawa Y et al: "Identification of a GPI-anchored type HDL-binding protein on human macrophages."Biochem Biophys Res Commun.. 272. 864-871 (2000)

[Publications] Yokota T,Oritani K,Funahashi T,Tenner AJ,Tomiyama Y,Matsuzawa Y et al.: "Adiponectin, a novel member of soluble defense collagens, negatively regulates the growth of myelo-monocytic progenitors and the functions of macrophages."Blood. 96. 1723-1732 (2000)

[Publications] Takahashi1 M,Arita Y,Yamagata K,Funahashi T,and Matsuzawa Y et al.: "Genomic structure and mutations in adipose-specific gene, adiponectin."Int.J.Obes.. 24. 861-868 (2000)

[Publications] Hotta K,Funahashi T,Arita Y,Takahashi M,Matsuzawa Y et al.: "Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients."Arterioscler Thromb Vasc Biol.. 20. 1595-1599 (2000)

[Publications] Okamoto Y,Arita Y,Nishida M,Funahashi T,Matsuzawa Y et al.: "An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls."Horm Metab Res.. 32. 47-50 (2000)

松澤佑次大阪大学, 医学系研究科, 教授 (70116101)