1999 Fiscal Year Annual Research Report

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-

Research Project

Project/Area Number	09307019
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, 講師 (60243242) 船橋徹大阪大学, 医学系研究科, 助手 (60243234) 西田誠大阪大学, 医学部・附属病院, 医員
Keywords	肥満 / 内臓脂肪 / 生活習慣病 / 動脈硬化 / adiponectin
Research Abstract	肥満、特に腹腔内内臓脂肪の蓄積は糖尿病、高脂血症、高血圧等の生活習慣病や動脈硬化症等の発症の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は過剰分泌によって直接血管病の発症に結びつくことが示されてきたが、本研究によりさらに私たちが新たに発見したadiponectinは上記の因子とは逆に肥満者において分泌不全がおこるユニークな分子であることが明らかになった。本年度はさらに本分子と病態、特に動脈硬化との関連において検討を進めた。adiponectinはコラーゲン族とのホモロジーを有するが血管内膜に存在するコラーゲンI,III,Vとの結合能を認め、血管傷害時に局所に集積した。また血管内皮細胞の接着分子発現を転写レベルで抑制し、動脈硬化の初期病変である内皮細胞への単球接着を抑制し、抗動脈硬化作用を有することが明らかになった。またadiponectin遺伝子変異を有する症例も冠動脈疾患を有することから本分子の抗動脈硬化作用が支持された。過栄養による肥満ではadiponectin分泌不全が血管病発症の一因となる可能性が考えられた。一方水チャネル分子であるaquaporin adiposeはグリセロール透過能を有し、絶食時に発現増加し、aquaporin阻害能を有する水銀イオンでグリセロール放出が抑制されることから、脂肪細胞においてグリセロール・チャネルとして機能していることが示された。肥満モデルにおいては本分子の発現が増加し,グリセロール放出が亢進していたが、これが肥満におけるグリセロール代謝異常や糖代謝異常に関することが示唆された。

Research Products
(23 results)

All Other

All Publications (23 results)

[Publications] 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. 211. 263-286 (1999)
[Publications] Y. Arita, S. Kihara, N. Ouch, M. Takahashi et al.: "Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity"Biochem. Biophys. Res. Commun.. 257. 79-85 (1999)
[Publications] Ouch N, Kihara S, Arita Yet al.: "Novel modulator for endothelial adhesion molecules : adipocyte-derived plasma protein adiponectin"Circulation. 100. 2473-2476 (1999)
[Publications] Inoue S. Fukuda K, Kudara et al.: "Augmented growth response to IGF-1 via increased IRS-1 in Chinese hamster ovary cells expressing kinase-negative insulin receptors"Diabetologia. 42. 763-772 (1999)
[Publications] Kayanoki Y, Higashiyama S, Suzuki K et al.: "The requirement of both intracellular reactive oxygen species and intracellular calcium elevation for the induction of heparin-binding EGF-like growth factor in vascular endothelia cells and smooth muscle cells"Biochem Biophys Res Commun.. 259. 50-55 (1999)
[Publications] Kiso S, Kawata 5, Tamura S.: "Effects of exogenous human heparin-binding epidermal growth factor-like growth factor on DNA synthesis of hepatocytes in normal mouse liver"Biochem Biophys Res Commun.. 259. 685-687 (1999)
[Publications] Kayanoki Y, Kawata S, Yamasaki E: "Reduced nitric oxide production by L-arginine deficiency in lysinuric protein intolerance exacerbates intravascular coagulation"Metabolism 48:1136-1140, 1999. 46. 1136-1140 (1999)
[Publications] Nozaki S, Tanaka T, Yamashita S 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. 192:129-135, 1999. 192. 129-135 (1999)
[Publications] Hirano K, Yamashita S, Nakagawa Y et al.: "Expression of human scavenger receptor class B type I in cultured human monocyte-derived macrophages and atherosclerotic lesions"Circ Res. 85. 108-116 (1999)
[Publications] Nakata A, Nakagawa Y, Nishida M et al.: "CD36, a novel receptor for oxidized low-density lipoproteins, is highly expressed on lipid-laden macrophages in human atherosclerotic aorta"Arterioscler Thromb Vasc Biol. 19. 1333-1339 (1999)
[Publications] Yang Q, Yamagata K, Yamamoto K et al.: "Structure/function studies of hepatocyte nuclear factor-1alpha, a diabetes-associated transcription factor"Biochem Biophys Res Commun.. 266. 196-202 (1999)
[Publications] Okita K, Yang Q, Yamagata K et al.: "Human insulin gene is a target gene of hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-1beta"Biochem Biophys Res Commun.. 263. 566-569 (1999)
[Publications] Yashiuchi I, Yamagata K, Yang Q et al.: "Three new mutations in the hepatocyte nuclear factor-1alpha gene in Japanese subjects with diabetes mellitus : clinical features and functional characterization"Diabetologia. 42. 621-626 (1999)
[Publications] Moriwaki M, Itoh N, Miyagawa J et al.: "Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with recent-onset Type I diabetes mellitus"Diabetologia. 42. 1332-1340 (1999)
[Publications] Imagawa A, Hanafusa T, Itoh N et al.: "Immunological abnormallties in islets at diagnosis paralleled further deterioration of glycaemic control in patients with recent-onset Type I (insulin-dependent) diabetes mellitus"Diabetologia. 42. 574-578 (1999)
[Publications] Yamada S. Zhu Q, Aihara Y et al.: "Cloning of cDNA and the gene encoding human hepatocyte unuclear factor (HNF)-3 beta and mutation screening in Jananese subjects with maturity-onset diabetes of the young"Diabetologia. 43. 121-124 (2000)
[Publications] Imagawa A, Hanafusa T, Miyagawa J et al.: "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] Hotta K, Matsukawa Y, Nishida M et al.: "Mutation in Bombesin Receptor Subtype-3 Gene is not a Major Cause of Obesity in he Japanese"Horm. Metab. Res.. (in press). (2000)
[Publications] Okamoto Y, Arita Y, Nishida M et al.: "An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls"Horm. Metab. Res.. (in press). (2000)
[Publications] Takahashi M, Arita Y, Yamagata K et al.: "Genomic structure and mutations in adipose-specific gene, adiponectin"lnt. J. Obes.. (in press). (2000)
[Publications] Funahashi T, Nakamura T, Shimomura I et al.: "Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity"Intern. Med. 38:202-206, 1999. 38. 202-206 (1999)
[Publications] Matsuzawa Y, Funahashi T, Nakamura T:: "Molecular mechanism of metabolic syndrome X: Contribution of adipocytokines, adipocyte-derived bioactive substances"Annals of the New York Academy of Sciences 892: 146-154, 1999. 892. 146-154 (1999)
[Publications] Matauzawa Y, Funahashi T, Kuriyama H, Kihara S: "Common Disease: Genetic and Pathogenetic Aspects of Multifactorial Diseases."Molecular mechanism of obesity-related diseases: importance of adipocytokine.. 7 (1999)

1999 Fiscal Year Annual Research Report

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-

Principal Investigator

松澤 佑次 大阪大学, 医学系研究科, 教授 (70116101)

Research Products

[Publications] 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. 211. 263-286 (1999)

[Publications] Y. Arita, S. Kihara, N. Ouch, M. Takahashi et al.: "Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity"Biochem. Biophys. Res. Commun.. 257. 79-85 (1999)

[Publications] Ouch N, Kihara S, Arita Yet al.: "Novel modulator for endothelial adhesion molecules : adipocyte-derived plasma protein adiponectin"Circulation. 100. 2473-2476 (1999)

[Publications] Inoue S. Fukuda K, Kudara et al.: "Augmented growth response to IGF-1 via increased IRS-1 in Chinese hamster ovary cells expressing kinase-negative insulin receptors"Diabetologia. 42. 763-772 (1999)

[Publications] Kiso S, Kawata 5, Tamura S.: "Effects of exogenous human heparin-binding epidermal growth factor-like growth factor on DNA synthesis of hepatocytes in normal mouse liver"Biochem Biophys Res Commun.. 259. 685-687 (1999)

[Publications] Kayanoki Y, Kawata S, Yamasaki E: "Reduced nitric oxide production by L-arginine deficiency in lysinuric protein intolerance exacerbates intravascular coagulation"Metabolism 48:1136-1140, 1999. 46. 1136-1140 (1999)

[Publications] Nozaki S, Tanaka T, Yamashita S 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. 192:129-135, 1999. 192. 129-135 (1999)

[Publications] Hirano K, Yamashita S, Nakagawa Y et al.: "Expression of human scavenger receptor class B type I in cultured human monocyte-derived macrophages and atherosclerotic lesions"Circ Res. 85. 108-116 (1999)

[Publications] Nakata A, Nakagawa Y, Nishida M et al.: "CD36, a novel receptor for oxidized low-density lipoproteins, is highly expressed on lipid-laden macrophages in human atherosclerotic aorta"Arterioscler Thromb Vasc Biol. 19. 1333-1339 (1999)

[Publications] Yang Q, Yamagata K, Yamamoto K et al.: "Structure/function studies of hepatocyte nuclear factor-1alpha, a diabetes-associated transcription factor"Biochem Biophys Res Commun.. 266. 196-202 (1999)

[Publications] Okita K, Yang Q, Yamagata K et al.: "Human insulin gene is a target gene of hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-1beta"Biochem Biophys Res Commun.. 263. 566-569 (1999)

[Publications] Yashiuchi I, Yamagata K, Yang Q et al.: "Three new mutations in the hepatocyte nuclear factor-1alpha gene in Japanese subjects with diabetes mellitus : clinical features and functional characterization"Diabetologia. 42. 621-626 (1999)

[Publications] Moriwaki M, Itoh N, Miyagawa J et al.: "Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with recent-onset Type I diabetes mellitus"Diabetologia. 42. 1332-1340 (1999)

[Publications] Imagawa A, Hanafusa T, Itoh N et al.: "Immunological abnormallties in islets at diagnosis paralleled further deterioration of glycaemic control in patients with recent-onset Type I (insulin-dependent) diabetes mellitus"Diabetologia. 42. 574-578 (1999)

[Publications] Yamada S. Zhu Q, Aihara Y et al.: "Cloning of cDNA and the gene encoding human hepatocyte unuclear factor (HNF)-3 beta and mutation screening in Jananese subjects with maturity-onset diabetes of the young"Diabetologia. 43. 121-124 (2000)

[Publications] Imagawa A, Hanafusa T, Miyagawa J et al.: "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] Hotta K, Matsukawa Y, Nishida M et al.: "Mutation in Bombesin Receptor Subtype-3 Gene is not a Major Cause of Obesity in he Japanese"Horm. Metab. Res.. (in press). (2000)

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

[Publications] Takahashi M, Arita Y, Yamagata K et al.: "Genomic structure and mutations in adipose-specific gene, adiponectin"lnt. J. Obes.. (in press). (2000)

[Publications] Funahashi T, Nakamura T, Shimomura I et al.: "Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity"Intern. Med. 38:202-206, 1999. 38. 202-206 (1999)

[Publications] Matsuzawa Y, Funahashi T, Nakamura T:: "Molecular mechanism of metabolic syndrome X: Contribution of adipocytokines, adipocyte-derived bioactive substances"Annals of the New York Academy of Sciences 892: 146-154, 1999. 892. 146-154 (1999)

[Publications] Matauzawa Y, Funahashi T, Kuriyama H, Kihara S: "Common Disease: Genetic and Pathogenetic Aspects of Multifactorial Diseases."Molecular mechanism of obesity-related diseases: importance of adipocytokine.. 7 (1999)

松澤佑次大阪大学, 医学系研究科, 教授 (70116101)