2003 年度実績報告書

インスリン抵抗性症候群発症基盤としてのアディポネクチンの発生工学的、遺伝的解析

研究課題

研究課題/領域番号	14370327
研究機関	大阪大学
研究代表者	船橋徹大阪大学, 医学系研究科, 講師 (60243234)
研究分担者	木原進士大阪大学, 医学系研究科, 助手 (20332736) 中村正大阪大学, 医学系研究科, 助手 (90252668)
キーワード	aiponectin / insulin resistance / vascular injury / atherosclerosis / metabolic syndrome / adipocyte / visceral fat
研究概要	糖尿病、高脂血症、高血圧などの動脈硬化危険因子を合併するマルチプルリスクファクター症候群は、インスリン抵抗性をしばしば示すためインスリン抵抗性症候群とも呼ばれるが、その本態は未だ明らかではない。私達は過栄養による腹腔内内臓脂肪蓄積がインスリン抵抗性症候群の上流に存在し、adipocytokine分泌異常が多彩な病態の基盤となっていることを明らかにしてきた。私達が発見したadiponectinは、脂肪細胞由来分泌蛋白でありながら、肥満、特に内臓脂肪蓄積時に血中濃度が低下する。本研究の目的は、adiponectinの生理作用を明らかにし、その分泌異常がインスリン抵抗性症候群においてどのような役割を果たすかを示すことにある。昨年度は、adiponectin欠損マウスがインスリン抵抗性、動脈硬化をきたしやすいモデルであること、ヒトにおいても血中濃度減少を伴う遺伝子変異がインスリン抵抗性症候群の形質を示すこと、を明らかにし、adiponectinはインスリン抵抗性、動脈硬化双方に防御的に働くbi-functional moleculeであることを示した。さらに今年度は、1)adiponectinが、1)NO合成酵素のリン酸化を介して内皮依存性血管弛緩反応に関与し、分泌不全が高血圧にも一部関与するであろうこと、2)抗炎症作用をもち、分泌不全により血管局所の炎症を惹起するとともに、脂肪組織CRP発現も増加すること、3)現在過栄養による消化器合併症として注目されている肝線維化や脂肪肝の発生にも関与すること、さらには4)乳癌など肥満に合併しやすいとされる腫瘍発生にも関わることが明らかになった。つまりadiponectin分泌不全は単にインスリン抵抗性に留まらず、過栄養に伴うとされる、多彩な病態に関与することが明らかになった。

研究成果
(34件)

すべてその他

すべて文献書誌 (34件)

[文献書誌] Brakenhielm E, et al.: "Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis"Proc Natl Acad Sci U S A. (in press). (2004)
[文献書誌] Sutinen J, et al.: "Effects of rosiglitazone on gene expression in subcutaneous adipose tissue in highly active antiretroviral therapy-associated lipodystrophy"Am J Physiol Endocrinol Metab. (in press). (2004)
[文献書誌] Kobayashi H, et al.: "Selective Suppression of Endothelial Cell Apoptosis by the High Molecular Weight Form of Adiponectin"Circ Res. (in press). (2004)
[文献書誌] Manuel Fernandez-Real J, et al.: "Adiponectin is independently associated with glycosylated haemoglobin"Eur J Endocrinol. 150. 201-205 (2004)
[文献書誌] Lopez-Bermejo A, et al.: "Adiponectin, hepatocellular dysfunction and insulin sensitivity"Clin Endocrinol. 60. 256-263 (2004)
[文献書誌] Sierksma A, et al.: "Effect of moderate alcohol consumption on adiponectin, tumor necrosis factor-alpha, and insulin sensitivity"Diabetes Care. 27. 184-189 (2004)
[文献書誌] Chudek J, et al.: "Plasma adiponectin concentration before and after successful kidney transplantation"Transplant Proc. 35. 2186-2189 (2003)
[文献書誌] Iwahashi H, et al.: "Plasma adiponectin levels in women with anorexia nervosa"Horm Metab Res.. 35. 537-540 (2003)
[文献書誌] Johanson EH, et al.: "Fat distribution, lipid accumulation in the liver, and exercise capacity do not explain the insulin resistance in healthy males with a family history for type 2 diabetes"J Clin Endocrinol Metab. 88. 4232-4238 (2003)
[文献書誌] Chen H, et al.: "Adiponectin stimulates production of nitric oxide in vascular endothelial cells"J Biol Chem. 278. 45021-45026 (2003)
[文献書誌] Lindsay RS, et al.: "Genome-wide linkage analysis of serum adiponectin in the Pima Indian population"Diabetes. 52. 2419-2425 (2003)
[文献書誌] Masaki T, et al.: "Peripheral, but not central, administration of adiponectin reduces visceral adiposity and upregulatas the expression of uncoupling protein in agouti yellow (Ayla) obese mice"Diabetes. 52. 2266-2273 (2003)
[文献書誌] Kamada Y, et al.: "Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin"Gastroenterology. 125. 1796-1807 (2003)
[文献書誌] Miyoshi Y, et al.: "Association of serum adiponectin levels with breast cancer risk"Clin Cancer Res.. 9. 5699-5704 (2003)
[文献書誌] Stefan N, et al.: "Plasma adiponectin and endogenous glucose production in humans"Diabetes Care. 26. 3315-3319 (2003)
[文献書誌] Nagasawa A, et al.: "Divergent effects of soy protein diet on the expression of adipocytokines"Biochem Biophys Res Commun. 311. 909-914 (2003)
[文献書誌] Yokota T, et al.: "Adiponectin, a fat cell product, influences the earliest lymphocyte precursors in bone marrow cultures by activation of the cyclooxygenase-prostaglandin pathway in stromal cells"J Immunol. 171. 5091-5099 (2003)
[文献書誌] Ouchi N, et al.: "Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein Kinase and Akt signaling in endothelial cells"J Biol Chem. 279. 1304-1309 (2003)
[文献書誌] Kojima S, et al.: "The variation of plasma concentrations of a novel, adipocyte derived protein, adiponectin, in patients with acute myocardial infarction"Heart. 89. 667 (2003)
[文献書誌] Pellme F, et al.: "Circulating, adiponectin levels are reduced in nonobese but insulin-resistant first-degree relatives of type 2 diabetic patients"Diabetes. 52. 1182-1186 (2003)
[文献書誌] Zoccali C, et al.: "Adiponectin is markedly increased in patients with nephrotic syndrome and is related to metabolic risk factors"Kidney Int. suppl. S98-S102 (2003)
[文献書誌] Sutinen J, et al.: "Circulating concentration of adiponectin and its expression in subcutaneous adipose tissue in patients with highly active antiretroviral therapy-associated lipodystrophy"J Clin Endocrinol Metab. 88. 1907-1910 (2003)
[文献書誌] Nagasawa A, et al.: "Effects of soy protein diet on the expression of adipose genes and plasma adiponectin"Horm Metab Res. 34. 635-639 (2003)
[文献書誌] Oppenheim WL, et al.: "Outcome of slipped capital femoral epiphysis in renal osteodystrophy"J Pediatr Orthop. 23. 169-174 (2003)
[文献書誌] Jansson PA, et al.: "A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin"FASEB J.. 17. 1434-1440 (2003)
[文献書誌] Ouchi N, et al.: "Association of hypoadiponectinemia with impaired vasoreactivity"Hypertension. 42. 231-234 (2003)
[文献書誌] Shimabukuro M, et al.: "Hypoadiponectinemia is closely linked to endothelial dysfunction in man"J Clin Endocrinol Metab. 88. 3236-3240 (2003)
[文献書誌] Iwaki M, et al.: "Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors"Diabetes. 52. 1655-1663 (2003)
[文献書誌] Krakoff J, et al.: "Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian"Diabetes Care. 26. 1745-1751 (2003)
[文献書誌] Kishida K, et al.: "Disturbed secretion of mutant adiponectin associated with the metabolic syndrome"Biochem Biophys Res Commun. 306. 286-292 (2003)
[文献書誌] Ouchi N, et al.: "Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue"Circulation. 107. 671-674 (2003)
[文献書誌] Kumada M, et al.: "Association of hypoadiponectinemia with coronary artery disease in men"Arterioscler Thromb Vasc Biol.. 23. 85-89 (2003)
[文献書誌] Adamczak M, et al.: "Decreased plasma adiponectin concentration in patients with essential hypertension"Am J Hypertens. 16. 72-75 (2003)
[文献書誌] Nemet D, et al.: "Adipocytokines, body composition, and fitness in children"Pediatr Res.. 53. 148-152 (2003)

2003 年度 実績報告書

インスリン抵抗性症候群発症基盤としてのアディポネクチンの発生工学的、遺伝的解析

研究代表者

船橋 徹 大阪大学, 医学系研究科, 講師 (60243234)

研究成果

[文献書誌] Brakenhielm E, et al.: "Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis"Proc Natl Acad Sci U S A. (in press). (2004)

[文献書誌] Sutinen J, et al.: "Effects of rosiglitazone on gene expression in subcutaneous adipose tissue in highly active antiretroviral therapy-associated lipodystrophy"Am J Physiol Endocrinol Metab. (in press). (2004)

[文献書誌] Kobayashi H, et al.: "Selective Suppression of Endothelial Cell Apoptosis by the High Molecular Weight Form of Adiponectin"Circ Res. (in press). (2004)

[文献書誌] Manuel Fernandez-Real J, et al.: "Adiponectin is independently associated with glycosylated haemoglobin"Eur J Endocrinol. 150. 201-205 (2004)

[文献書誌] Lopez-Bermejo A, et al.: "Adiponectin, hepatocellular dysfunction and insulin sensitivity"Clin Endocrinol. 60. 256-263 (2004)

[文献書誌] Sierksma A, et al.: "Effect of moderate alcohol consumption on adiponectin, tumor necrosis factor-alpha, and insulin sensitivity"Diabetes Care. 27. 184-189 (2004)

[文献書誌] Chudek J, et al.: "Plasma adiponectin concentration before and after successful kidney transplantation"Transplant Proc. 35. 2186-2189 (2003)

[文献書誌] Iwahashi H, et al.: "Plasma adiponectin levels in women with anorexia nervosa"Horm Metab Res.. 35. 537-540 (2003)

[文献書誌] Johanson EH, et al.: "Fat distribution, lipid accumulation in the liver, and exercise capacity do not explain the insulin resistance in healthy males with a family history for type 2 diabetes"J Clin Endocrinol Metab. 88. 4232-4238 (2003)

[文献書誌] Chen H, et al.: "Adiponectin stimulates production of nitric oxide in vascular endothelial cells"J Biol Chem. 278. 45021-45026 (2003)

[文献書誌] Lindsay RS, et al.: "Genome-wide linkage analysis of serum adiponectin in the Pima Indian population"Diabetes. 52. 2419-2425 (2003)

[文献書誌] Masaki T, et al.: "Peripheral, but not central, administration of adiponectin reduces visceral adiposity and upregulatas the expression of uncoupling protein in agouti yellow (Ayla) obese mice"Diabetes. 52. 2266-2273 (2003)

[文献書誌] Kamada Y, et al.: "Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin"Gastroenterology. 125. 1796-1807 (2003)

[文献書誌] Miyoshi Y, et al.: "Association of serum adiponectin levels with breast cancer risk"Clin Cancer Res.. 9. 5699-5704 (2003)

[文献書誌] Stefan N, et al.: "Plasma adiponectin and endogenous glucose production in humans"Diabetes Care. 26. 3315-3319 (2003)

[文献書誌] Nagasawa A, et al.: "Divergent effects of soy protein diet on the expression of adipocytokines"Biochem Biophys Res Commun. 311. 909-914 (2003)

[文献書誌] Yokota T, et al.: "Adiponectin, a fat cell product, influences the earliest lymphocyte precursors in bone marrow cultures by activation of the cyclooxygenase-prostaglandin pathway in stromal cells"J Immunol. 171. 5091-5099 (2003)

[文献書誌] Ouchi N, et al.: "Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein Kinase and Akt signaling in endothelial cells"J Biol Chem. 279. 1304-1309 (2003)

[文献書誌] Kojima S, et al.: "The variation of plasma concentrations of a novel, adipocyte derived protein, adiponectin, in patients with acute myocardial infarction"Heart. 89. 667 (2003)

[文献書誌] Pellme F, et al.: "Circulating, adiponectin levels are reduced in nonobese but insulin-resistant first-degree relatives of type 2 diabetic patients"Diabetes. 52. 1182-1186 (2003)

[文献書誌] Zoccali C, et al.: "Adiponectin is markedly increased in patients with nephrotic syndrome and is related to metabolic risk factors"Kidney Int. suppl. S98-S102 (2003)

[文献書誌] Sutinen J, et al.: "Circulating concentration of adiponectin and its expression in subcutaneous adipose tissue in patients with highly active antiretroviral therapy-associated lipodystrophy"J Clin Endocrinol Metab. 88. 1907-1910 (2003)

[文献書誌] Nagasawa A, et al.: "Effects of soy protein diet on the expression of adipose genes and plasma adiponectin"Horm Metab Res. 34. 635-639 (2003)

[文献書誌] Oppenheim WL, et al.: "Outcome of slipped capital femoral epiphysis in renal osteodystrophy"J Pediatr Orthop. 23. 169-174 (2003)

[文献書誌] Jansson PA, et al.: "A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin"FASEB J.. 17. 1434-1440 (2003)

[文献書誌] Ouchi N, et al.: "Association of hypoadiponectinemia with impaired vasoreactivity"Hypertension. 42. 231-234 (2003)

[文献書誌] Shimabukuro M, et al.: "Hypoadiponectinemia is closely linked to endothelial dysfunction in man"J Clin Endocrinol Metab. 88. 3236-3240 (2003)

[文献書誌] Iwaki M, et al.: "Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors"Diabetes. 52. 1655-1663 (2003)

[文献書誌] Krakoff J, et al.: "Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian"Diabetes Care. 26. 1745-1751 (2003)

[文献書誌] Kishida K, et al.: "Disturbed secretion of mutant adiponectin associated with the metabolic syndrome"Biochem Biophys Res Commun. 306. 286-292 (2003)

[文献書誌] Ouchi N, et al.: "Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue"Circulation. 107. 671-674 (2003)

[文献書誌] Kumada M, et al.: "Association of hypoadiponectinemia with coronary artery disease in men"Arterioscler Thromb Vasc Biol.. 23. 85-89 (2003)

[文献書誌] Adamczak M, et al.: "Decreased plasma adiponectin concentration in patients with essential hypertension"Am J Hypertens. 16. 72-75 (2003)

[文献書誌] Nemet D, et al.: "Adipocytokines, body composition, and fitness in children"Pediatr Res.. 53. 148-152 (2003)

2003 年度実績報告書

船橋徹大阪大学, 医学系研究科, 講師 (60243234)