2002 Fiscal Year Annual Research Report

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

Research Project

Project/Area Number	14370327
Research Institution	Osaka University
Principal Investigator	船橋徹大阪大学, 医学系研究科, 講師 (60243234)
Co-Investigator(Kenkyū-buntansha)	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)
Keywords	aiponectin / insulin resistance / vascular injury / atherosclerosis / metabolic syndrome / adipocyte / visceral fat
Research Abstract	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の中に、これらの危険因子が偶然合併するのではなく、共通の発症基盤をもつ独立した病態が想定されている。このような病態では、インスリンに対する反応不全、すなわち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ているが、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、環境負荷による脂肪組織発現遺伝子発現異常こそが多彩な病態の基盤となっていると考え検討を行ってきた。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(adipocytokine)を分泌する内分泌細胞であり、過栄養による分泌異常が病態に関わることを明らかにした。この過程で発見したadiponectinは、1)血管平滑節細胞の増殖抑制や、マクロファージ泡沫化抑制などの抗動脈硬化作用を有しており、2)血管傷害時に局所に集積する。3)脂肪細胞特異的な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、などの特徴を有している。本研究の目的は、この脂肪細胞由来分子の生体防御作用を明らかにし、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。本年度は、まずadiponectin欠損マウスを作成し、その形質を検討した。1)Adiponectinノックアウトマウスは発育に異常はなく体重も正常であった。筋肉FATP遺伝子発現の減少、脂肪組織TNFa遺伝子発現の増加を認めたが、通常食下ではインスリン感受性も正常であった。しかし高脂肪高ショ糖食負荷により強いインスリン抵抗性が惹起された(Nat Med 2002)。インスリン感受性が正常な通常食下でも、内皮傷害を加えると強い内膜肥厚が生じた(JBC 2002)。つまりadiponectinノックアウトマウスは環境負荷によりインスリン抵抗性、動脈硬化をきたしやすいモデルマウスと考えられた。2)一方ヒトAdiponectin遺伝子異常のスクリーニング過程で、血中濃度減少を伴うミスセンス変異を見い出した。この変異は糖尿病患者に有意に多く、非糖尿病群でも高血圧、脂質代謝異常、動脈硬化疾患合併するインスリン抵抗性症候群の形質を示した(Diabetes 2002)。一方3)血中adiponectin濃度の高い群は、その後の糖羅病罹患率(Lancet 2002)や心血管イベント発症率(JASN 2002)が低いことが示された。4)さらに動脈硬化を好発するアポE欠損マウス(このモデルはインスリン感受性に異常はない)にヒトAdiponectinを高発現し血中濃度を上昇させたところ、粥状動脈硬化巣の進展が抑制された(Circulation 2002)。これらの検討より脂肪細胞分泌因子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であることが明らかになった。ここで重要なことは1)この分子は環境負荷が加わった時に働く防御因子であること、2)動脈硬化防御作用はインスリン抵抗性防御作用とは独立していることである。過栄養により多彩なadipocytokineの分泌異常がおこり、adiponectin分泌不全は動脈硬化発症の一翼をになうと考えられる。このような動脈硬化易発症状態を「インスリン抵抗性」症候群と呼ぶ妥当性については再考の余地があると考えられる。

Research Products

(26 results)

All Other

All Publications (26 results)

[Publications] Kumada M et al.: "Association of hypoadiponectinemia with coronary artery disease in men"Arterioscler Thromb Vasc Biol.. 23. 85-89 (2003)
[Publications] Adamczak M et al.: "Decreased plasma adiponectin concentration in patients with essential hypertension"Am J Hypertens. 16. 72-75 (2003)
[Publications] Nemet D et al.: "Adipocytokines, body composition, and fitness in children"Pediatr Res.. 53. 148-152 (2003)
[Publications] Mallamaci F et al.: "Adiponectin in essential hypertension"J Nephrol. 15. 507-511 (2002)
[Publications] Okamoto Y et al.: "Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice"Circulation. 106. 2767-2770 (2002)
[Publications] Yang WS et al.: "Plasma adiponectin levels in overweight and obese Asians"Obes Res. 10. 1104-1110 (2002)
[Publications] Stefan N et al.: "Plasma adiponectin levels are not associated with fat oxidation in humans"Obes Res. 10. 1016-1020 (2002)
[Publications] Stefan N et al.: "Plasma adiponectin concentrations in children : relationships with obesity and insulinemia"J Clin Endocrinol Metab.. 67. 4652-4656 (2002)
[Publications] Vozarova B et al.: "Low plasma adiponectin concentrations do not predict weight gain in humans"Diabetes. 51. 2964-2967 (2002)
[Publications] Kuriyama H et al.: "Coordinated regulation of fat-specific and liver-specific glycerol channels, aquaporin adipose and aquaporin 9"Diabetes. 51. 2915-2921 (2002)
[Publications] Nishizawa H et al.: "Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein"Diabetes. 51. 2734-2741 (2002)
[Publications] Imagawa A et al.: "Elevated serum concentration of adipose-derived factor, adiponectin, in patients with type 1 diabetes"Diabetes Care. 25. 1665-1666 (2002)
[Publications] Delporte ML et al.: "Pre-and post-translational negative effect of beta-adrenoceptor agonists on adiponectin secretion : in vitro and in vivo studies"Biochem J.. 367. 677-685 (2002)
[Publications] Matsuda M et al.: "Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis"J Biol Chem.. 277. 37487-37491 (2002)
[Publications] Lindsay RS et al.: "Adiponectin and development of type 2 diabetes in the Pima Indian population"Lancet. 360. 57-58 (2002)
[Publications] Kondo H et al.: "Association of adiponectin mutation with type 2 diabetes : a candidate gene for the insulin resistance syndrome"Diabetes. 51. 2325-2358 (2002)
[Publications] Arita Y et al.: "Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell"Circulation. 105. 2893-2898 (2002)
[Publications] Maeda N et al.: "Diet-induced insulin resistance in mice lacking adiponectin/ACRP30"Nat Med.. 8. 731-737 (2002)
[Publications] Stefan N et al.: "Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans"Diabetes. 51. 1884-1888 (2002)
[Publications] Yokota T et al.: "Paracrine regulation of fat cell formation in bone marrow cultures via adiponectin and prostaglandins"J Clin Invest. 109. 1303-1310 (2002)
[Publications] Kondo H et al.: "Human aquaporin adipose(AQPap)gene. Genomic structure, promoter analysis and functional mutation"Eur J Biochem.. 269. 1814-1826 (2002)
[Publications] Matsumoto S et al.: "Increased plasma HB-EGF associated with obesity and coronary artery disease"Biochem Biophys Res Commun. 292. 781-786 (2002)
[Publications] Yang WS et al.: "Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients"Diabetes Care. 25. 376-380 (2002)
[Publications] Nagaretani H et al.: "Visceral fat is a major contributor for multiple risk factor clustering in Japanese men with impaired glucose tolerance"Diabetes Care. 24. 2127-2133 (2002)
[Publications] Nishizawa H: "Small heterodimer partner, an orphan nuclear receptor, augments PPARg transactivation"J Biol Chem. 277. 1586-1592 (2002)
[Publications] Zoccali C et al.: "Adiponectin, the most abundant adipocyte-derived protein, is functionally related to metabolic risk factors and predicts cardiovascular outcomes in end stage renal disease"J Am Soc Nephrol. 109. 134-141 (2002)

2002 Fiscal Year Annual Research Report

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

Principal Investigator

船橋 徹 大阪大学, 医学系研究科, 講師 (60243234)

Research Products

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

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

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

[Publications] Mallamaci F et al.: "Adiponectin in essential hypertension"J Nephrol. 15. 507-511 (2002)

[Publications] Okamoto Y et al.: "Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice"Circulation. 106. 2767-2770 (2002)

[Publications] Yang WS et al.: "Plasma adiponectin levels in overweight and obese Asians"Obes Res. 10. 1104-1110 (2002)

[Publications] Stefan N et al.: "Plasma adiponectin levels are not associated with fat oxidation in humans"Obes Res. 10. 1016-1020 (2002)

[Publications] Stefan N et al.: "Plasma adiponectin concentrations in children : relationships with obesity and insulinemia"J Clin Endocrinol Metab.. 67. 4652-4656 (2002)

[Publications] Vozarova B et al.: "Low plasma adiponectin concentrations do not predict weight gain in humans"Diabetes. 51. 2964-2967 (2002)

[Publications] Kuriyama H et al.: "Coordinated regulation of fat-specific and liver-specific glycerol channels, aquaporin adipose and aquaporin 9"Diabetes. 51. 2915-2921 (2002)

[Publications] Nishizawa H et al.: "Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein"Diabetes. 51. 2734-2741 (2002)

[Publications] Imagawa A et al.: "Elevated serum concentration of adipose-derived factor, adiponectin, in patients with type 1 diabetes"Diabetes Care. 25. 1665-1666 (2002)

[Publications] Delporte ML et al.: "Pre-and post-translational negative effect of beta-adrenoceptor agonists on adiponectin secretion : in vitro and in vivo studies"Biochem J.. 367. 677-685 (2002)

[Publications] Matsuda M et al.: "Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis"J Biol Chem.. 277. 37487-37491 (2002)

[Publications] Lindsay RS et al.: "Adiponectin and development of type 2 diabetes in the Pima Indian population"Lancet. 360. 57-58 (2002)

[Publications] Kondo H et al.: "Association of adiponectin mutation with type 2 diabetes : a candidate gene for the insulin resistance syndrome"Diabetes. 51. 2325-2358 (2002)

[Publications] Arita Y et al.: "Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell"Circulation. 105. 2893-2898 (2002)

[Publications] Maeda N et al.: "Diet-induced insulin resistance in mice lacking adiponectin/ACRP30"Nat Med.. 8. 731-737 (2002)

[Publications] Stefan N et al.: "Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans"Diabetes. 51. 1884-1888 (2002)

[Publications] Yokota T et al.: "Paracrine regulation of fat cell formation in bone marrow cultures via adiponectin and prostaglandins"J Clin Invest. 109. 1303-1310 (2002)

[Publications] Kondo H et al.: "Human aquaporin adipose(AQPap)gene. Genomic structure, promoter analysis and functional mutation"Eur J Biochem.. 269. 1814-1826 (2002)

[Publications] Matsumoto S et al.: "Increased plasma HB-EGF associated with obesity and coronary artery disease"Biochem Biophys Res Commun. 292. 781-786 (2002)

[Publications] Yang WS et al.: "Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients"Diabetes Care. 25. 376-380 (2002)

[Publications] Nagaretani H et al.: "Visceral fat is a major contributor for multiple risk factor clustering in Japanese men with impaired glucose tolerance"Diabetes Care. 24. 2127-2133 (2002)

[Publications] Nishizawa H: "Small heterodimer partner, an orphan nuclear receptor, augments PPARg transactivation"J Biol Chem. 277. 1586-1592 (2002)

[Publications] Zoccali C et al.: "Adiponectin, the most abundant adipocyte-derived protein, is functionally related to metabolic risk factors and predicts cardiovascular outcomes in end stage renal disease"J Am Soc Nephrol. 109. 134-141 (2002)

船橋徹大阪大学, 医学系研究科, 講師 (60243234)