2002 Fiscal Year Annual Research Report

脂肪細胞由来の多彩な新規生理活性物質の発見と生理学的及び病理学的意義の解明-Common disease発症の分子機構における脂肪細胞中心説の確立-

Research Project

Project/Area Number	12307022
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, 助教授 (60243242) 船橋徹大阪大学, 医学系研究科, 講師 (60243234) 酒井尚彦大阪大学, 医学系研究科, 助手 (80294073) 平岡久豊大阪大学, 医学系研究科, 助手 (00273681)
Keywords	内臓脂肪 / adipocytokine / adiponectin / aquaporin adipose
Research Abstract	糖尿病や動脈硬化疾患などcommon disease共通の発症基盤として、過栄養による脂肪蓄積が大きな位置を占める。私達は腹腔内内臓脂肪蓄積が上記病態と密接に繋がり、内臓脂肪の分子特性を明らかにすることがcommon disease発症機構解明に貢献すると考え脂肪細胞発現遺伝子解析を行った。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ることを見い出した。本研究の目的は、栄養状態に応じて活発に増減する脂肪細胞が、巨大な内分泌臓器としてadipocytokineを分泌し生態防御に貢献するが、肥満になると分泌が変化し、栄養状態と関連するcommon disease発症に関わること(脂肪細胞中心仮説)を証明することである。本年度は、まず私達が発見したadiponectinについて、本分子の欠損が生体に及ぼす影響を検討した。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)。血管形態も正常であったが、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common disease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メタボリックシンドロームの形質を示した(Diabetes 2002)。一方3)血中adiponectin濃度の高い群は、その後の糖尿病罹患率(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)そこで本分子の臨床応用のため、動脈硬化を好発するアポ E 欠損マウスにヒト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の低下はcommon disease発症促進的に、上昇は抑制的に作用することが明らかになった。やはり私達が同定しグリセロールチャネルとしての意義を明らかにしてきたaquaporin adipose(AQPap)については、1)本分子の機能欠失変異がヒトにおいてみいだされ、本例では絶食運動時の血中グリセロール増加が抑えられており(Eur J Biochem 2002)、AQPapの生体でのグリセロールチャネルとしての意義が確認された。2)AQPapが肝臓のAQP9と連動して摂食状態で発現が変化し、糖新生基質であるグリセロールの内臓脂肪から肝臓への経路を調節しているが、内臓脂肪蓄積状態ではこの調節が障害されていて高血糖の一因となっていることが示された(Diabetes 2002)。以上の検討により、common disease発症における脂肪細胞中心仮説の妥当性が証明されたと考える。

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 Vase 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 tunctionally 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

脂肪細胞由来の多彩な新規生理活性物質の発見と生理学的及び病理学的意義の解明-Common disease発症の分子機構における脂肪細胞中心説の確立-

Principal Investigator

松澤 佑次 大阪大学, 医学系研究科, 教授 (70116101)

Research Products

[Publications] Kumada M et al.: "Association of hypoadiponectinemia with coronary artery disease in men"Arterioscler Thromb Vase 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 tunctionally related to metabolic risk factors and predicts cardiovascular outcomes in end stage renal disease"J Am Soc Nephrol.. 109. 134-141 (2002)

松澤佑次大阪大学, 医学系研究科, 教授 (70116101)