2003 Fiscal Year Annual Research Report

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-

Research Project

Project/Area Number	13137206
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)
Keywords	内臓脂肪 / aquaporin adipose / glycerol / insulin resistance
Research Abstract	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。

Research Products

(34 results)

All Other

All Publications (34 results)

[Publications] 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)
[Publications] 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)
[Publications] Kobayashi H, et al.: "Selective Suppression of Endothelial Cell Apoptosis by the High Molecular Weight Form of Adiponectin"Circ Res.. (in press). (2004)
[Publications] Manuel Fernandez-Real J, et al.: "Adiponectin is independently associated with glycosylated haemoglobin."Eur J Endocrinol.. 150. 201-205 (2004)
[Publications] Lopez-Bermejo A, et al.: "Adiponectin, hepatocellular dysfunction and insulin sensitivity."Clin Endocrinol. 60. 256-263 (2004)
[Publications] Sierksma A, et al.: "Effect of moderate alcohol consumption on adiponectin, tumor necrosis factor-alpha, and insulin sensitivity."Diabetes Care.. 27. 184-189 (2004)
[Publications] Chudek J, et al.: "Plasma adiponectin concentration before and after successful kidney transplantation."Transplant Proc. 35. 2186-2189 (2003)
[Publications] Iwahashi H, et al.: "Plasma adiponectin levels in women with anorexia nervosa."Horm Metab Res.. 35. 537-540 (2003)
[Publications] 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)
[Publications] Chen H, et al.: "Adiponectin stimulates production of nitric oxide in vascular endothelial cells."J Biol Chem.. 278. 45021-45026 (2003)
[Publications] Rindsay RS, et al.: "Genome-wide linkage analysis of serum adiponectin in the Pima Indian population."Diabetes.. 52. 2419-2425 (2003)
[Publications] 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)
[Publications] Kamada Y, et al.: "Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin."Gastroenterology.. 125. 1796-1807 (2003)
[Publications] Miyoshi Y, et al.: "Association of serum adiponectin levels with breast cancer risk."Clin Cancer Res.. 9. 5699-5704 (2003)
[Publications] Stefan N, et al.: "Plasma adiponectin and endogenous glucose production in humans."Diabetes Care.. 26. 3315-3319 (2003)
[Publications] Nagasawa A, et al.: "Divergent effects of soy protein diet on the expression of adipocytokines"Biochem Biophys Res Commun.. 311. 909-914 (2003)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] Oppenheim WL, et al.: "Outcome of slipped capital femoral epiphysis in renal osteodystrophy."J Pediatr Orthop.. 23. 169-174 (2003)
[Publications] 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)
[Publications] Ouchi N, et al.: "Association of hypoadiponectinemia with impaired vasoreactivity."Hypertension. 42. 231-234 (2003)
[Publications] Shimabukuro M, et al.: "Hypoadiponectinemia is closely linked to endothelial dysfunction in man."J Clin Endocrinol Metab.. 88. 3236-3240 (2003)
[Publications] Iwaki M, et al.: "Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors."Diabetes.. 52. 1655-1663 (2003)
[Publications] Krakoff J, et al.: "Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian."Diabetes Care.. 26. 1745-1751 (2003)
[Publications] Kishida K, et al.: "Disturbed secretion of mutant adiponectin associated with the metabolic syndrome."Biochem Biophys Res Commun.. 306. 286-292 (2003)
[Publications] Ouchi N, et al.: "Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue."Circulation. 107. 671-674 (2003)
[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)

2003 Fiscal Year Annual Research Report

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-

Principal Investigator

船橋 徹 大阪大学, 医学系研究科, 講師 (60243234)

Research Products

[Publications] 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)

[Publications] 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)

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

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

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

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

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

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

[Publications] 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)

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

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

[Publications] 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)

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

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

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

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

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

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

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

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

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

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

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

[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)

船橋徹大阪大学, 医学系研究科, 講師 (60243234)