2001 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

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	糖尿病や動脈硬化性疾患など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、内脚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(adipccytokine)を分泌する内分泌細胞であることを見出した。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を分泌し生体防御に貢献するが、肥満時に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(脂肪細胞中心性仮説)を証明することである。本年度はまず1)私達が同定し、動脈硬化との関連を明らかにしてきたadiponeclinのインスリン抵抗性への関与を検討した。これまで糖尿病の多くを占める2型糖尿病で血中adiponectin濃度が低値を示すことを報告.したが、グルコースクランプ法によりadiponectin血中濃度はインスリン感受性と良好な正相関を示すこと、体脂肪蓄積が進むと血中濃度が速やかに低下しインスリン抵抗性発症に先行することが示され(Diabetes2001a, JCEM2001b)、adiponeclinは血管機能、インスリン感受性双方に影響を与え、内脚脂肪蓄積による分泌不全が多彩な病態の中心的な役割を果たすと考えられた。2)グリセロールも脂肪細胞から分泌される重要な生理活性物質で、私達はaquaporin familyに属する新規分子aquaporin adiposeがグリセロールチャネルとして機能し、プロモーター解析によりインスリンによる発現抑制の特異的エレメントを同定して報告した(JBC2001a)。3)皮下脂肪量は年齢とともに減少し、相対的な内脚脂肪蓄積が病態形成に関わっているかも知れない。脂肪組織特異的レクチン様分子、galectin-12をクローニングした。Galectin familyは細胞外に分泌され、細胞増殖、接着に関与するが、galectin-12強発現によりアポトーシスが誘導された(JBC2001b)。4)上記脂肪細胞特異的分子の発現は転写因子PPARgによって制御されている(Diabetes2001b, JBC2001c)。近年核受容体分子は様々なcofactorによって調節を受けることが明らかになった。SHP(short heterodimer partner)は種々の転写因子の抑制因子として知られているが、最近、SHP遺伝子異常がインスリン抵抗性を示すことが報告された。私達はSHPが脂肪組織に発現し、他の転写因子とは異なってPPARgに対じては促進因子として働くことを示した(JBC2001d)。

Research Products
(18 results)

All Other

All Publications (18 results)

[Publications] 0uchi N, et al.: "Adipocyte-derived plasma protein, adiponectin, supppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages"Circulation. 103. 1057-1063 (2001)
[Publications] Hotta K, et al.: "Circulating concentrations of the adipocyte protein, adiponenctin, are decreascd in parallel with reduced insulin sensitivity during the progression to type-2 diabetes in rhesus monkeys"Diabetes. 50. 1126-1133 (2001)
[Publications] Weycr C, et al.: "Hypoadiponcctinemia in obesity and type 2 diabetes: Evidence for a role of insulin resistance and/or hyperinsulinemia"J. Clin. Endocriml. Metab.. 86. 1930-1935 (2001)
[Publications] Maeda N, et al.: "PPARγ ligands increase expression and plasma concentrations of adiponecitir an adipose-derived protein"Diabetes. 50. 2094-2099 (2001)
[Publications] Comuzzie AG, et a.: "The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome"J. Clin. Endocrinol. Metab.. 86. 4321-4325 (2001)
[Publications] Yamg WS, et al.: "Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin"J. Clin. Endocrinol. Metab.. 86. 3815-3819 (2001)
[Publications] Halleux CM, et al.: "Secretion of Adiponectin and Regulation of apM1 Gene Expression in Human Visceral Adipose Tissue"Biochem Biophys Res Commun.. 288. 1102-1107 (2001)
[Publications] Nakamura T, et al.: "Thiazolidinedione derivatives improves fat distribution and multiple risk factors in subjects with visceral fat accumulation-blind placebo-controlled trial"Diabetes Res Clin Pract.. 54. 181-190 (2001)
[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 (2001)
[Publications] Zoccali C, et al.: "Adiponectin, the most adipocyte-derived protein, is functionally related to metabolic risk factors and predicts cardiovascular outcomes in end stage renal disease"J Am Soc Nephrol.. 13. 134-141 (2002)
[Publications] Yamg 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] Kishida K et al.: "Genomic structre and insulin-mediated repression of the aquaporin adipose(AQPap), adipose-specific glycerol channel"J Biol Chem.. 276. 36251-36260 (2001)
[Publications] Kishida K et al.: "Enhancement of the aquaporin adipose (AQPap) gene expression by a peroxisome proliferator-activated receptorγ"J Biol Chem.. 276. 48572-48579 (2001)
[Publications] Nakamura T et al.: "Magnitude of sustained risk for ischemic heart disease in Japanese employees: a case-control study"Jpn. Circ. J.. 65. 11-17 (2001)
[Publications] Kobayashi H, et al.: "Visceral fat accumulation to insulin resistance, small-sized low-density lipoprotein, and progression of coronary artery disease in middle-aged non-obese Japanese men"Jpn. Circ. J.. 65. 193-199 (2001)
[Publications] Hotta K, et al.: "Galectin-12 an adipose-expressed galectin-like molecule possessing apoptosis-inducing activity"J Bio1 Chem.. 276. 34089-34097 (2001)
[Publications] Takahashi M et al.: "The expression of sparc in adipose tissue and its increased plasma concentration in patients with coronary artery disease"Obcs Res.. 9. 388-393 (2001)
[Publications] Nishizawa H et al.: "Small heterodimer partner, an orphan nuclear receptor, augments PPARg transactivation"J Biol Chcm. 277. 1586-1592 (2002)

2001 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

Principal Investigator

松澤 佑次 大阪大学, 医学系研究科, 教授 (70116101)

Research Products

[Publications] 0uchi N, et al.: "Adipocyte-derived plasma protein, adiponectin, supppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages"Circulation. 103. 1057-1063 (2001)

[Publications] Hotta K, et al.: "Circulating concentrations of the adipocyte protein, adiponenctin, are decreascd in parallel with reduced insulin sensitivity during the progression to type-2 diabetes in rhesus monkeys"Diabetes. 50. 1126-1133 (2001)

[Publications] Weycr C, et al.: "Hypoadiponcctinemia in obesity and type 2 diabetes: Evidence for a role of insulin resistance and/or hyperinsulinemia"J. Clin. Endocriml. Metab.. 86. 1930-1935 (2001)

[Publications] Maeda N, et al.: "PPARγ ligands increase expression and plasma concentrations of adiponecitir an adipose-derived protein"Diabetes. 50. 2094-2099 (2001)

[Publications] Comuzzie AG, et a.: "The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome"J. Clin. Endocrinol. Metab.. 86. 4321-4325 (2001)

[Publications] Yamg WS, et al.: "Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin"J. Clin. Endocrinol. Metab.. 86. 3815-3819 (2001)

[Publications] Halleux CM, et al.: "Secretion of Adiponectin and Regulation of apM1 Gene Expression in Human Visceral Adipose Tissue"Biochem Biophys Res Commun.. 288. 1102-1107 (2001)

[Publications] Nakamura T, et al.: "Thiazolidinedione derivatives improves fat distribution and multiple risk factors in subjects with visceral fat accumulation-blind placebo-controlled trial"Diabetes Res Clin Pract.. 54. 181-190 (2001)

[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 (2001)

[Publications] Zoccali C, et al.: "Adiponectin, the most adipocyte-derived protein, is functionally related to metabolic risk factors and predicts cardiovascular outcomes in end stage renal disease"J Am Soc Nephrol.. 13. 134-141 (2002)

[Publications] Yamg 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] Kishida K et al.: "Genomic structre and insulin-mediated repression of the aquaporin adipose(AQPap), adipose-specific glycerol channel"J Biol Chem.. 276. 36251-36260 (2001)

[Publications] Kishida K et al.: "Enhancement of the aquaporin adipose (AQPap) gene expression by a peroxisome proliferator-activated receptorγ"J Biol Chem.. 276. 48572-48579 (2001)

[Publications] Nakamura T et al.: "Magnitude of sustained risk for ischemic heart disease in Japanese employees: a case-control study"Jpn. Circ. J.. 65. 11-17 (2001)

[Publications] Kobayashi H, et al.: "Visceral fat accumulation to insulin resistance, small-sized low-density lipoprotein, and progression of coronary artery disease in middle-aged non-obese Japanese men"Jpn. Circ. J.. 65. 193-199 (2001)

[Publications] Hotta K, et al.: "Galectin-12 an adipose-expressed galectin-like molecule possessing apoptosis-inducing activity"J Bio1 Chem.. 276. 34089-34097 (2001)

[Publications] Takahashi M et al.: "The expression of sparc in adipose tissue and its increased plasma concentration in patients with coronary artery disease"Obcs Res.. 9. 388-393 (2001)

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

松澤佑次大阪大学, 医学系研究科, 教授 (70116101)