1998 年度実績報告書

肥満症(特に内臓脂肪型肥満)の病態とその分子機構-多彩な成人病発症を基盤として-

研究課題

研究課題/領域番号	09307019
研究機関	大阪大学
研究代表者	松沢佑次大阪大学, 医学部, 教授 (70116101)
研究分担者	西田誠大阪大学, 医学部・附属病院, 医員中村正大阪大学, 医学部, 助手 (90252668) 山下静也大阪大学, 医学部, 助手 (60243242) 船橋徹大阪大学, 医学部, 助手 (60243234)
キーワード	肥満 / 内臓脂肪 / 生活習慣病 / 動脈硬化 / adiponectin
研究概要	最もcommonな成人病(生活習慣病)の糖尿病、高脂血症、高血圧、動脈硬化症等の発症には過栄養に基づく肥満即ち脂肪組織の過剰蓄積が大きな基盤となっている。本研究では脂肪組織の分子生物学的特性を明らかにすることよって、脂肪蓄積が多彩な病態を発症せしむる分子機構を解明しようとするものである。これまで明らかになったこととして、脂肪細胞は従来考えられていたような単なる受動的なエネルギー備蓄細胞ではなく、多彩な生理活性物質を合成・放出する分泌細胞であり、その中で特に内臓脂肪の蓄積とともに多量分泌されるPAI-1やHB-EGFのような線溶系調節因子や平滑筋細胞増殖因子が直接血管病の発症に結びつくことが示された。本年度は、脂肪組織の大規模ランダム・シークエンスによって発見した脂肪細胞特異的に発現する新規分子で、病態発症と強く関連すると思われるadiponectinとaquaporin adiposeとについて解析した。adiponectinは脂肪細胞特異的な新規分泌蛋白である。正常者血漿中にadiponectinは5-10μg/mlの高濃度で存在し、予想とは逆に肥満、特に内臓脂肪型で著しい低値を示した。本分子はコラーゲン様構造を持ち血管内膜内に存在するコラーゲンI,III,Vと強い結合能を持つ。またTNFα刺激による内皮細胞の単球接着、増殖因子による平滑筋細胞の細胞増殖抑制作用を持つことが証明された。つまりadiponectinは脂肪細胞から分泌される動脈硬化防御因子であり、肥満時における減少は重要な血管病発症の分子メカニズムの一つと考えられた。aquaporinadiposeは水チャネル・ファミリーに属する新規分子で脂肪細胞に高発現していた。本分子は水透過能を示すとともに、非イオン性小分子であるグリセロール透過能も有していた。脂肪組織における発現は肥満時及び絶食時に充進していた。次年度はadiponectinの作用機構、aquaporin adiposcのグリセロール・チャネルとしての分子機構を明らかにしていく予定である。

研究成果
(26件)

すべてその他

すべて文献書誌 (26件)

[文献書誌] Y.Arita,S.Kihara,N.Ouchi,M.Takahashi et al.: "paradoxical decrease of an adipose-specific protein,adiponectin,in obesity" Biochem.Biophys.Res.Commun.(in press). (1999)
[文献書誌] T.Yoshizumi,T.Nakamura,M.Yamane,W.Islam.A.H.M.,et al.: "A standardized technique for the measurement of abdominal fat based on computed tomography" Radiology. (in press). (1999)
[文献書誌] H.Kuriyama,S.Yamashita,I.Shimomura,T.Funahashi,et al: "Enhanced expression of hepatic acyl-CoA synthetase and microsomal triglyceride transfer protein mRNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation" Hepatology. 27(2). 562-557 (1998)
[文献書誌] S.Kihara,N.Ouchi,T.Funahashi,E.Shinohara,et al.: "Troglitazone enhances glucose uptake and inhibits mitogen-activated protein kinase in human aortic smooth muscle cells" Atherosclerosis. 136(1). 163-168 (1998)
[文献書誌] E.Shinohara,S.Kihara,N.Ouchi,T.Funahashi,et al.: "Troglitazone suppresses intimal formation following ballon injury in insulin-resistant Zucker fatty rats" Atherosclerosis. 136(2). 275-279 (1998)
[文献書誌] F,Matsuura,S.Yamashita,T.Nakamura,M.Nishida,et al.: "Effect of visceral fat accumulation on uric acid metabolism in male obese subjects:visceral fat obesity is linked more closely to overproduction of uric acid than subcutaneous fat obesity" Metabolism. 47(8). 929-933 (1998)
[文献書誌] T.Nakagawa,S.Nozaki,M.Nishida,J.M.Yakub,et al.: "Oxidized LDL increases and interferon-gamma decreases expression of CD36 in human monocyte-derived macrophages" Arterioscler.Thrmb.Vasc.Biol.18(8). 1350-1357 (1998)
[文献書誌] T.Maruyama,Y.Miyake,T.Yamamura,S.Tajima,et al.: "A novel point mutation in a splice acceptor site of intron 1 of the human low density lipoprotein receptor gene which causes severe hypercholesterolemia:an unexpected absence of exon skippinng" Human Mutation. 12. 480-483 (1998)
[文献書誌] K.Fukuchi,S.Nozaki,T.Yoshizumi,T.Uehara,et al.: "Enhanced myocardial glucose uptake in individuals with a deficiency in long-chain fatty acid transport(CD36 deficiency)" J.Nucl.Med.,. (in press). (1999)
[文献書誌] S.Nozaki,T.Tanaka,S.Yamashita,K.Sohmiya,et al.: "CD36 mediates long-chain fatty acid transport in human myocardium:complete myocardial accumulation defect of radiolabeled long-chain fatty acid analog in subjects with CD36 deficiency." Mol.Cell.Biochem.(in press). (1999)
[文献書誌] A.Nakata,Y.Namagawa,M.Nishida,S.Nozaki,et al.: "CD36,a novel receptor for oxidized low density lipoproteins,is highly expressed on lipidladen macrophages in human atherosclerotic aorta" Arterioscler.Thromb.Vasc.(in press). (1999)
[文献書誌] F.Matsuura,S.Yamashita,H.Hirano,M.Ishigami,et al.: "Activation of monocytes in vivo causes intracellular accumulation of lipoprotein-lipids and marked hypocholesterolemia-possible pathogenesis of nerobiotic xanthogranuloma-" Atherosclerosis. (in press). (1999)
[文献書誌] S.Takami,S.Yamashita,S.Kihara,M.Ishigami,et al.: "Lipoprotein(a)enhances the expression of intercellular adhesion molecule-1 in cultured human umbilical vein endothelial cells" Circulation. 97(8). 721-728 (1998)
[文献書誌] Yamagata-K;Yang-Q;Yamamoto-K;Iwahashi-H,et al.: "Mutation P29lfsinsC in the transcription factor hepatocyte nuclear factor-lalpha is dominant negative." Diabetes. 47(8). 1231-1235 (1998)
[文献書誌] I.Toshiuchi,et al: "Three new mutations in the hepatocyte nuclear factor-1 α gene in Japanese subjects with diabetes mellitus;Clinical features and functional characterization." Diabetologia. (in press). (1999)
[文献書誌] A.Imagawa et al: "In situ immunological abnormalities in islets parallelled further deteriolation of glycemic control in recent-onset type I(insulin-dependent)diabetes mellitus patients" Diabetologia. (in press). (1999)
[文献書誌] K.Aoyama et al: "Stromal cell CD9 regulates differentiation of hematopoietic stem/progenitor cells." Blood. (in press). (1999)
[文献書誌] H.Kashiwagi,Y.Tomiyama,S.Tadokoro et al.: "A mutation in the extracellular cystein-rich repeat region of the β3 subunit activates integrin αIIbβ3 and ανβ3." Blood. (in press). (1999)
[文献書誌] S.Tadokoro,Y.Tomiyama,S.Honda,M.Arai,et al.: "A Gln747->Pro substitution in the Ilb subunit is responsible for a moderate Ilbbeta3 deficiency in Glanzmann thrombasthenia." Blood. 92(8). 2750-2758 (1998)
[文献書誌] M.Shiraga,Y.Tomiyama,S.Honda,et al.: "Involvement of Na+/Ca2+exchanger in inside-out signaling through the platelet integrin IIbbeta3." Blood. 92(10). 3710-3720 (1998)
[文献書誌] S.Honda,Y.Tomiyama,T,Aoki,M.Shiraga,et al.: "Association between ligand-induced conformational changes of integrin IIb β3 and IIbβ3-mediated intracellular Ca2+signaling." Blood. 92(10). 3675-3683 (1998)
[文献書誌] S.Honda,Y.Tomiyama,M.Shiraga,S.Tadokoro,et al.: "A two-amino acid insertion in the Cys146-Cys167 loop of the alphaIIb subunit is associated with a variant of Glanzmann thrombasthenia.Critical role of Asp163 in ligand binding." J.Clin.Invest.102(6). 1183-1192 (1998)
[文献書誌] Y.Okajima,I.Matsumura,T.Nishiura,K.Hashimoto,et al.: "Insulin-like growth factor-I augments erythropoietin-induced proliferation through enhanced tyrosine phosphorylation of STAT5." J.Biol.Chem.273(36). 22877-22883 (1998)
[文献書誌] T.Yokota,K.Oritani,H.Mitsui,K.Aoyama,et al: "Growth-supporting activities of fibronectin on hematopoietic stem/progenitor cells in vitro and in vivo:structural requirement for fibronectin activities of CS1 and cell-binding domains." Blood. 91(9). 3263-3272 (1998)
[文献書誌] Fukuda,S.Kawata,S.Tamura,Y.Matsuda,et al.: "Transforming growth factor-β1-induced degradation of activated Src tyrosine kinase in rat fibroblasts" Oncogene. 17(26). 3349-3356 (1998)
[文献書誌] K.Fukuda,S.Kawata,S.Tamura,Y.Matsuda,et al.: "Altered regulation of Sre tyrosine kinase by transforming growth factor-β1 in a human hepatoma cell line." Hepatology. 28(9). 796-804 (1998)

1998 年度 実績報告書

肥満症(特に内臓脂肪型肥満)の病態とその分子機構-多彩な成人病発症を基盤として-

研究代表者

松沢 佑次 大阪大学, 医学部, 教授 (70116101)

研究成果

[文献書誌] Y.Arita,S.Kihara,N.Ouchi,M.Takahashi et al.: "paradoxical decrease of an adipose-specific protein,adiponectin,in obesity" Biochem.Biophys.Res.Commun.(in press). (1999)

[文献書誌] T.Yoshizumi,T.Nakamura,M.Yamane,W.Islam.A.H.M.,et al.: "A standardized technique for the measurement of abdominal fat based on computed tomography" Radiology. (in press). (1999)

[文献書誌] H.Kuriyama,S.Yamashita,I.Shimomura,T.Funahashi,et al: "Enhanced expression of hepatic acyl-CoA synthetase and microsomal triglyceride transfer protein mRNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation" Hepatology. 27(2). 562-557 (1998)

[文献書誌] S.Kihara,N.Ouchi,T.Funahashi,E.Shinohara,et al.: "Troglitazone enhances glucose uptake and inhibits mitogen-activated protein kinase in human aortic smooth muscle cells" Atherosclerosis. 136(1). 163-168 (1998)

[文献書誌] E.Shinohara,S.Kihara,N.Ouchi,T.Funahashi,et al.: "Troglitazone suppresses intimal formation following ballon injury in insulin-resistant Zucker fatty rats" Atherosclerosis. 136(2). 275-279 (1998)

[文献書誌] F,Matsuura,S.Yamashita,T.Nakamura,M.Nishida,et al.: "Effect of visceral fat accumulation on uric acid metabolism in male obese subjects:visceral fat obesity is linked more closely to overproduction of uric acid than subcutaneous fat obesity" Metabolism. 47(8). 929-933 (1998)

[文献書誌] T.Nakagawa,S.Nozaki,M.Nishida,J.M.Yakub,et al.: "Oxidized LDL increases and interferon-gamma decreases expression of CD36 in human monocyte-derived macrophages" Arterioscler.Thrmb.Vasc.Biol.18(8). 1350-1357 (1998)

[文献書誌] T.Maruyama,Y.Miyake,T.Yamamura,S.Tajima,et al.: "A novel point mutation in a splice acceptor site of intron 1 of the human low density lipoprotein receptor gene which causes severe hypercholesterolemia:an unexpected absence of exon skippinng" Human Mutation. 12. 480-483 (1998)

[文献書誌] K.Fukuchi,S.Nozaki,T.Yoshizumi,T.Uehara,et al.: "Enhanced myocardial glucose uptake in individuals with a deficiency in long-chain fatty acid transport(CD36 deficiency)" J.Nucl.Med.,. (in press). (1999)

[文献書誌] S.Nozaki,T.Tanaka,S.Yamashita,K.Sohmiya,et al.: "CD36 mediates long-chain fatty acid transport in human myocardium:complete myocardial accumulation defect of radiolabeled long-chain fatty acid analog in subjects with CD36 deficiency." Mol.Cell.Biochem.(in press). (1999)

[文献書誌] A.Nakata,Y.Namagawa,M.Nishida,S.Nozaki,et al.: "CD36,a novel receptor for oxidized low density lipoproteins,is highly expressed on lipidladen macrophages in human atherosclerotic aorta" Arterioscler.Thromb.Vasc.(in press). (1999)

[文献書誌] F.Matsuura,S.Yamashita,H.Hirano,M.Ishigami,et al.: "Activation of monocytes in vivo causes intracellular accumulation of lipoprotein-lipids and marked hypocholesterolemia-possible pathogenesis of nerobiotic xanthogranuloma-" Atherosclerosis. (in press). (1999)

[文献書誌] S.Takami,S.Yamashita,S.Kihara,M.Ishigami,et al.: "Lipoprotein(a)enhances the expression of intercellular adhesion molecule-1 in cultured human umbilical vein endothelial cells" Circulation. 97(8). 721-728 (1998)

[文献書誌] Yamagata-K;Yang-Q;Yamamoto-K;Iwahashi-H,et al.: "Mutation P29lfsinsC in the transcription factor hepatocyte nuclear factor-lalpha is dominant negative." Diabetes. 47(8). 1231-1235 (1998)

[文献書誌] I.Toshiuchi,et al: "Three new mutations in the hepatocyte nuclear factor-1 α gene in Japanese subjects with diabetes mellitus;Clinical features and functional characterization." Diabetologia. (in press). (1999)

[文献書誌] A.Imagawa et al: "In situ immunological abnormalities in islets parallelled further deteriolation of glycemic control in recent-onset type I(insulin-dependent)diabetes mellitus patients" Diabetologia. (in press). (1999)

[文献書誌] K.Aoyama et al: "Stromal cell CD9 regulates differentiation of hematopoietic stem/progenitor cells." Blood. (in press). (1999)

[文献書誌] H.Kashiwagi,Y.Tomiyama,S.Tadokoro et al.: "A mutation in the extracellular cystein-rich repeat region of the β3 subunit activates integrin αIIbβ3 and ανβ3." Blood. (in press). (1999)

[文献書誌] S.Tadokoro,Y.Tomiyama,S.Honda,M.Arai,et al.: "A Gln747->Pro substitution in the Ilb subunit is responsible for a moderate Ilbbeta3 deficiency in Glanzmann thrombasthenia." Blood. 92(8). 2750-2758 (1998)

[文献書誌] M.Shiraga,Y.Tomiyama,S.Honda,et al.: "Involvement of Na+/Ca2+exchanger in inside-out signaling through the platelet integrin IIbbeta3." Blood. 92(10). 3710-3720 (1998)

[文献書誌] S.Honda,Y.Tomiyama,T,Aoki,M.Shiraga,et al.: "Association between ligand-induced conformational changes of integrin IIb β3 and IIbβ3-mediated intracellular Ca2+signaling." Blood. 92(10). 3675-3683 (1998)

[文献書誌] S.Honda,Y.Tomiyama,M.Shiraga,S.Tadokoro,et al.: "A two-amino acid insertion in the Cys146-Cys167 loop of the alphaIIb subunit is associated with a variant of Glanzmann thrombasthenia.Critical role of Asp163 in ligand binding." J.Clin.Invest.102(6). 1183-1192 (1998)

[文献書誌] Y.Okajima,I.Matsumura,T.Nishiura,K.Hashimoto,et al.: "Insulin-like growth factor-I augments erythropoietin-induced proliferation through enhanced tyrosine phosphorylation of STAT5." J.Biol.Chem.273(36). 22877-22883 (1998)

[文献書誌] T.Yokota,K.Oritani,H.Mitsui,K.Aoyama,et al: "Growth-supporting activities of fibronectin on hematopoietic stem/progenitor cells in vitro and in vivo:structural requirement for fibronectin activities of CS1 and cell-binding domains." Blood. 91(9). 3263-3272 (1998)

[文献書誌] Fukuda,S.Kawata,S.Tamura,Y.Matsuda,et al.: "Transforming growth factor-β1-induced degradation of activated Src tyrosine kinase in rat fibroblasts" Oncogene. 17(26). 3349-3356 (1998)

[文献書誌] K.Fukuda,S.Kawata,S.Tamura,Y.Matsuda,et al.: "Altered regulation of Sre tyrosine kinase by transforming growth factor-β1 in a human hepatoma cell line." Hepatology. 28(9). 796-804 (1998)

1998 年度実績報告書

松沢佑次大阪大学, 医学部, 教授 (70116101)