メタボリックシンドロームの分子基盤としての脂肪細胞分泌因子の臨床的実験的研究

2006 Fiscal Year Annual Research Report

• Project/Area Number: 17390271
• Research Institution: Osaka University
• Principal Investigator: 船橋 徹 大阪大学, 医学系研究科, 助教授 (60243234)
• Co-Investigator(Kenkyū-buntansha): 中村 正 大阪大学, 医学系研究科, 講師 (90252668) ; 木原 進士 大阪大学, 医学系研究科, 助手 (20332736)
• Keywords: 遺伝子 / 内科 / 循環器・高血圧 / プロテオーム / 糖尿病

Research Abstract

メタボリックシンドロームはインスリン抵抗性、脂質代謝異常、高血圧を合併する病態で動脈硬化性疾患のcommonな発症基盤である。私たちは脂肪組織が多彩な生理活性物質を分泌する巨大な内分泌臓器であることを見出して、数々の新規遺伝子を発見し、アデイポサイトカインと概念付けた。本研究では、Adiponectin,Visfatin,Glycerolという3つの脂肪細胞分泌因子に焦点をあて、メタボリックシンドロームの病態を臨床的、実験的に解析するものである。平成18年度は以下のAdiponectinに関してひきつづき検討を行なった。その低下が動脈硬化性疾患の発症進展に関わることをこれまで臨床的、実験的に示してきた。血中濃度低下のメカニズムの一つとして内臓脂肪蓄積時に全身性に酸化ストレス物質が増加していることを示した(Circ J)。実験的にも蓄積した脂肪組織で酸化ストレス物質が増加しているが、アンジオテンシン受容体阻害剤が脂肪組織酸化ストレスを減少させ、Adiponectinを含めたアデイポサイトカイン分泌異常を改善することを明らかにした(Kid Int)。またAdiponectin欠乏は血管内皮機能にも影響を与え、ノックアウトマウスでは食塩感受性の高血圧をきたすことを明らかにし、メタボリックシンドロームにおける高血圧症発症の新しいメカニズムの一つを示した(Hypertension)。臨床的に低Adiponectin血症は冠動脈の複雑性病変と関連すること(JACC)、急性心筋梗塞発症後の血中濃度低下が、その後の生命予後にも関わることを示した(Atherosclerosis)。さらに最近注目されている慢性腎疾患(CKD)の心血管疾患リスクとしての意義も示した(Am J Cardiol)。

Research Products

• [Journal Article] Pravastatin improved glucose metabolism associated with increasing plasma adiponectin in patients with impaired glucose tolerance and coronary artery disease. (2007)
  • Author(s): Sugiyama S, Fukushima H, Kugiyama K, Maruyoshi H, Kojima S, Funahashi T, Sakamoto T, Horibata Y, Watanabe K, Koga H, Sugamura K, Otsuka F, Shimomura I, Ogawa H.
  • Journal Title: Atherosclerosis. (In press)
• [Journal Article] Future adverse cardiac events can be predicted by persistently low plasma adiponectin concentrations in men and marked reductions of adiponectin in women after acute myocardial infarction. (2007)
  • Author(s): Kojima S, Funahashi T, Otsuka F, Maruyoshi H, Yamashita T, Kajiwara I, Shimomura H, Miyao Y, Fujimoto K, Sugiyama S, Sakamoto T, Yoshimura M, Ogawa H.
  • Journal Title: Atherosclerosis. (In press)
• [Journal Article] A novel index of insulin resistance determined from the homeostasis model assessment index and adiponectin levels in Japanese subjects. (2007)
  • Author(s): Matsuhisa M, Yamasaki Y, Emoto M, Shimabukuro M, Funahashi T, Matsuzawa Y.
  • Journal Title: Diabetes Res Clin Pract (In press)
• [Journal Article] Lower total fasting plasma adiponectin concentrations are associated with higher metabolic rates (2006)
  • Author(s): Pannacciulli N, Bunt JC, Ortega E, Funahashi T, Salbe AD, Bogardus C, Krakoff J
  • Journal Title: J Clin Endocrinol Metab. 91 Pages: 1600-1603
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adiponectin replenishment ameliorates obesity-related hypertension. (2006)
  • Author(s): Ohashi K, Kihara S, Ouchi N, Kumada M, Fujita K, Hiuge A, Hibuse T, Ryo M, Nishizawa H, Maeda N, Maeda K, Shibata R, Walsh K, Funahashi T, Shimomura I
  • Journal Title: Hypertension. 47 Pages: 1108-1116
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adiponectin downregulates its own production and the expression of its AdipoR2 receptor in transgenic mice (2006)
  • Author(s): Bauche IB, Ait El Mkadem S, Rezsohazy R, Funahashi T, Maeda N, Miranda LM, Brichard SM
  • Journal Title: Biochem Biophys Res Commun 345 Pages: 1414-1424
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adiponectin and renal function, and implication as a risk of cardiovascular disease. (2006)
  • Author(s): Iwashima Y, Horio T, Kumada M, Suzuki Y, Kihara S, Rakugi H, Kawano Y, Funahashi T, Ogihara T
  • Journal Title: Am J Cardiol. 98 Pages: 1603-1608
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Plasma adiponectin levels are associated with coronary lesion complexity in men with coronary artery disease (2006)
  • Author(s): Otsuka F, Sugiyama S, Kojima S, Maruyoshi H, Funahashi T, Matsui K, Sakamoto T, Yoshimura M, Kimura K, Umemura S, Ogawa H
  • Journal Title: J Am Coll Cardiol 48 Pages: 1155-1162
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adiponectin concentration in umbilical cord serum is positively associated with the weight ratio of fetus to placenta. (2006)
  • Author(s): Kadowaki K, Waguri M, Nakanishi I, Miyashita Y, Nakayama M, Suehara N, Funahashi T, Shimomura I, Fujita T
  • Journal Title: J Clin Endocrinol Metab 91 Pages: 5090-5094
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Systemic oxidative stress is associated with visceral fat accumulation and the metabolic syndrome. (2006)
  • Author(s): Fujita K, Nishizawa H, Funahashi T, Shimomura I, Shimabukuro M
  • Journal Title: Circ J. 7011 Pages: 1437-1442
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adiponectin and inflammatory markers in peripheral arterial occlusive disease. (2006)
  • Author(s): Iwashima Y, Horio T, Suzuki Y, Kihara S, Rakugi H, Kangawa K, Funahashi T, Ogihara T, Kawano Y.
  • Journal Title: Atherosclerosis. 188 Pages: 384-390
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adiponectin acts as an endogenous antithrombotic factor. (2006)
  • Author(s): Kato H, Kashiwagi H, Shiraga M, Tadokoro S, Kamae T, Ujiie H, Honda S, Miyata S, Ijiri Y, Yamamoto J, Maeda N, Funahashi T, Kurata Y, Shimomura I, Tomiyama Y, Kanakura Y.
  • Journal Title: Arterioscler Thromb Vasc Biol. 26 Pages: 224-230
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of amino-terminal region of adiponectin as a physiologically functional domain. (2006)
  • Author(s): Ujiie H, Oritani K, Kato H, Yokota T, Takahashi I, Maeda T, Masaie H, Ichii M, Kamada Y, Tamura S, Kihara S, Funahashi T, Tomiyama Y, Kanakura Y.
  • Journal Title: J Cell Biochem. 98 Pages: 194-207
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adiponectin levels and arteriosclerotic risk factors in pediatric renal transplant recipients. (2006)
  • Author(s): Bakkaloglu SA, Soylemezoglu O, Buyan N, Oktar SO, Funahashi T, Pasaoglu H, Elhan AH, Peru H, Hasanoglu E.
  • Journal Title: Pediatr Transplant. 10 Pages: 187-192
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Associations of adiponectin levels with incident impaired glucose metabolism and type 2 diabetes in older men and women : the hoorn study. (2006)
  • Author(s): Snijder MB, Heine RJ, Seidell JC, Bouter LM, Stehouwer CD, Nijpels G, Funahashi T, Matsuzawa Y, Shimomura I, Dekker JM.
  • Journal Title: Diabetes Care. 29 Pages: 2498-2503
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Blockade of Angiotensin II type-1 receptor reduces oxidative stress in adipose tissue and ameliorates adipocytokine dysregulation. (2006)
  • Author(s): Kurata A, Nishizawa H, Kihara S, Maeda N, Sonoda M, Okada T, Ohashi K, Hibuse T, Fujita K, Yasui A, Hiuge A, Kumada M, Kuriyama H, Shimomura I, Funahashi T.
  • Journal Title: Kidney Int. 70 Pages: 1717-1724
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] High expression of leptin receptor mRNA in breast cancer tissue predicts poor prognosis for patients with high, but not low, serum leptin levels (2006)
  • Author(s): Miyoshi Y, Funahashi T, Tanaka S, Taguchi T, Tamaki Y, Shimomura I, Noguchi S.
  • Journal Title: Int J Cancer 118 Pages: 1414-1419
• [Journal Article] Adiponectin deficiency exacerbates lipopolysaccharide/D-galactosamine-induced liver injury in mice. (2006)
  • Author(s): Matsumoto H, Tamura S, Kamada Y, Kiso S, Fukushima J, Wada A, Maeda N, Kihara S, Funahashi T, Matsuzawa Y, Shimomura I, Hayashi N
  • Journal Title: World J Gastroenterol. 12 Pages: 3352-3358
• [Journal Article] Effect of adiponectin on murine colitis induced by dextran sulfate sodium. (2006)
  • Author(s): Nishihara T, Matsuda M, Araki H, Oshima K, Kihara S, Funahashi T, Shimomura I
  • Journal Title: Gastroenterology 131 Pages: 853-861
• [Journal Article] Visfatin in adipocytes is upregulated by hypoxia through HIF lalpha-dependent mechanism. (2006)
  • Author(s): Segawa K, Fukuhara A, Hosogai N, Morita K, Okuno Y, Tanaka M, Nakagawa Y, Kihara S, Funahashi T, Komuro R, Matsuda M, Shimomura I
  • Journal Title: Biochem Biophys Res Commun 349 Pages: 875-882