2003 年度実績報告書

脂肪細胞水チャネル分子、aquaporin adiposeの解析 -生理機能およびグリセロール代謝における意義-

研究課題

研究課題/領域番号	13137206
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)
キーワード	内臓脂肪 / aquaporin adipose / glycerol / insulin resistance
研究概要	Aquaporin(AQP)は生物界に広く存在する水チャネルで、細胞内外の浸透圧変化の調節に重要な役割を果たしている。AQPファミリーはさらに、水透過能のみを有する狭義のAQPと、水とともにグリセロール透過能を併せ持つaquaglyceroporinの2つのsubfamilyに分類される。aquaporin adipose(AQPap)は、私達が脂肪組織発現遺伝子の大規模シークエンス解析の過程で発見したaquaglyceroporinに属する新規AQP分子である。本研究はAQPapをモデルとして、AQP分子のグリセロールチャネルとしての意義を確立しようとするものである。本年度までの研究により、脂肪組織AQPap発現は、脂肪細胞分化のマスターレギュレーターと考えられているPPARγにより発現が制御されており、脂肪分解抑制ホルモンであるインスリンはAQPap遺伝子のプロモーター領域のinsulin responsive elementを介し,発現を抑制すること、肝臓のAQP9と連動して、グリセロール流入を調節し、糖新生に関与することなどが明らかになった。以上の観察から、AQPapは生体においてまさしくグリセロールチャネルとして機能する可能性が考えられた。本年度はAQPapを遺伝的に欠損するノックアウトマウスの樹立に成功し、その形質を解析した。AQPapノックアウトマウスは空腹時の血漿グリセロール濃度が低下しており、血糖値も低値であった。遊離脂肪酸濃度は正常であった。AQPap発現を欠損する脂肪細胞ではカテコラミン刺激に対するグリセロール分泌が障害されていた。in vivoにおいても、ノックアウトマウスにβ3agonistを投与しても野生型に比し、血中グリセロール濃度の上昇が障害されていた。AQPapの重要性は、ノックアウトマウスが絶食により容易に低血糖をきたすことで明らかになった。つまり絶食時の糖新生の基質としてグリセロールが重要であり、AQPap欠損により効率的にグリセロールが放出されないために低血糖に陥ると考えられた。グリセロールチャネルの存在とその意義が初めて明らかにされ、現在結果を投稿中である。

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] Rindsay 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 upregulates the expression of uncoupling protein in agouti yellow (Ay/a) 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 Vase 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

脂肪細胞水チャネル分子、aquaporin adiposeの解析 -生理機能およびグリセロール代謝における意義-

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] Rindsay 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 upregulates the expression of uncoupling protein in agouti yellow (Ay/a) 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 Vase 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)