Discovery of adipose specific glycerol channel and its application to obesity therapy

• Project/Area Number: 12557090
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 展開研究
• Research Field: Endocrinology
• Research Institution: Osaka University
• Principal Investigator: MATSUZAWA Yuji Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (70116101)
• Co-Investigator(Kenkyū-buntansha): NAKAMURA Tadashi Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (90252668) ; YAMASHITA Shizuya Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (60243242) ; FUNAHASHI Touru Osaka University, Graduate School of Medicine, Lecturer, 医学系研究科, 講師 (60243234) ; SAKAI Naohiko Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (80294073) ; HIRAOKA Hisatoyo Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (00273681)
• Project Period (FY): 2000 – 2001
• Project Status: Completed (Fiscal Year 2001)
• Budget Amount: ¥12,200,000 (Direct Cost: ¥12,200,000); Fiscal Year 2001: ¥5,700,000 (Direct Cost: ¥5,700,000); Fiscal Year 2000: ¥6,500,000 (Direct Cost: ¥6,500,000)
• Keywords: visceral fat / aquaporin adipose / glycerol / insulin resistance / 肥満 / グリセロール

Research Abstract

Aquaporin adipose is a fat-specific glycerol channel.
We identified the PPRE (peroxisome proliferator response element) in the promoter region of the mouse AQPap gene. Binding and activation of PPARγ (peroxisome proliferator activated receptor_γ) to this element was suggested to explain the fat-specific expression of AQPap mRNA.
AQPap gene expression was negatively regulated by insulin in vivo and in tissue cultures. In the analysis of AQPap promoter, we showed there was an insulin negative response element composed of seven nucleotides.
In the search of genetic mutations of AQPap in 160 human subjects, we found three types of missense mutation (R12C, V59L, G264V) and two types of silent mutations (A103A, Q250G). By the functional analysis, the G264V-type AQPap was not capable of transporting glycerol using the xenopus oocyte system. The homozygous subject for G264V AQPap failed to raise the concentrations of plasma glycerol in response to vigorous exercise, while there was an equivalent serge of plasma adrenalin, which suggested that the AQPap is mediating the glycerol release from fat by exercise in human.
We are now investigating the phenotypes of AQPap knockout mice to clarify the physiological significance of AQPap and glycerol metabolism in whole body.

Research Products

• [Publications] Kondo H et al.: "Human AQPap gene ; the genomic structure, promoter analysis and functional mutations"Eur. J. Biol. Chem.. (in press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kishida K et al.: "Genomic structure and insulin-mediated repression of the aquaporin adipose (AQPap), adipose-specific glycerol channel"J. Biol. Chem.. 276. 36251-36260 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kishida K et al.: "Enhancement of the aquaporin adipose (AQPap) gene expression by a peroxisome proliferator-activated receptor γ"J. Biol. Chem.. 276. 48572-48579 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kishida K et al.: "Aquaporin adipose, a putative glycerol channel in adipocytes"J. Biol. Chem.. 275. 20896-20902 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kishida, K., Kuriyama, H., Funahashi, T., Shimomura, I., Kihara, S., Ouchi, N., Nishida, M., Nishizawa, H., Matsuda, M., Takahashi, M., Hotta, K., Nakamura, T., Yamashita, S., Tochino, Y., and Matsuzawa, Y.: "Aquaporin adipose, a putative glycerol channel in adipocytes"J Biol Chem.. 275. 20896-20902 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kishida K, Shimomura I, Kondo H, Kuriyama H, Makino Y, Nishizawa H, Maeda N, Matsuda M, Kihara S, Kurachi Y, Funahashi T, Matsuzawa Y.: "Genomic Structure and Insulin-mediated Repression of the Aquaporin Adipose (AQPap), Adipose-specific Glycerol Channel"J Biol Chem.. 276. 36251-36260 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kishida K, Shimomura I, Nishizawa H, Maeda N, Kuriyama H, Kondo H, Matsuda M, Nagaretani H, Ouchi N, Hotta K, Kihara S, Kadowaki T, Funahashi T, Matsuzawa Y.: "Enhancement of the aquaporin adipose (AQPap) gene expression by a peroxisome proliferator-activated receptor g"J Biol Chem.. 276. 48572-48579 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kondo H, Shimomura I, Kishida K, Nishizawa H, Maeda N, Kuriyama H, Matsuda M, Nagaretani H, Kihara S, Funahashi T, and Mitsuzawa Y.: "Human AQPap gene ; the genomic structure, promoter analysis and functional mutations"Eur. J. Biol. Chem.. (in press). (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kondo H et al.: "Human AQPap gene ; the genomic structure, promoter analysis and functional mutations"Eur.J.Biol.Chem.. (in press).
• [Publications] Kishida K et al.: "Genomic structure 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] Kishida K et al.: "Aquaporin adipose, a putative glycerol channel in adipocytes"J Biol Chem.. 275. 20896-20902 (2000)
• [Publications] Hotta K,Funahashi T,Bodkin NL,Ortmeyer HK,Arita Y,Hansen BC,and Matsuzawa Y: "Circulating concentrations of the adipocyte protein, adiponectin, are decreased in parallel with reduced insulin sensitivity during the progression to type-2 diabetes in rhesus monkeys."Diabetes. (in press). (2001)
• [Publications] Weyer C,Funahashi T,Tanaka S,Hotta K,Matsuzawa Y,Pratley RE,Tataranni PA: "Hypoadiponectinemia in obesity and type 2 diabetes : Evidence for a role of insulin resistance and/or hyperinsulinemia."J.Clin.Endocrinol.Metab. (in press). (2001)
• [Publications] Nakamura T,Tsubono Y,Takemura K,Funahashi T,Matsuzawa Y et al.: "Magnitude of sustained multiple risk factors for ischemic heart disease in Japanese employees"Jpn.Circ.J.. (in press). (2001)
• [Publications] Kobayashi H,Nakamura T,Miyaoka K,Nishida M,Funahashi T,Matsuzawa Y et al: "Visceral fat accumulation contributes to insulin resistance, small-sized low-density lipo-protein, and progression of coronary artery disease in middle-aged non-obese Japanese men."Jpn.Circ.J.. (in press). (2001)
• [Publications] Ouchi N,Kihara S,Arita Y,Nishida M,Funahashi T,Matsuzawa Y et al.: "Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-deriyed macrophages."Circulation. 103. 1057-1063 (2001)
• [Publications] Nishigori H,Tomura H,Tonooka N,Yamagata K,Matsuzawa Y,Takeda J. et al: "Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects."Proc Natl Acad Sci USA.. 98. 575-580 (2001)
• [Publications] Imagawa A,Hanafusa T,Miyagawa J,Matsuzawa Y.: "A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies."N Engl J Med.. 342. 301-307 (2000)
• [Publications] Ouchi N,Kihara S,Arita Y,Okamoto Y,Funahashi T,and Matsuzawa Y et al.: "Adiponectin, adipocyte-derived plasma protein, inhibits endothelial NF-kB signaling through cAMP-dependent pathway."Circulation. 102. 1296-1301 (2000)
• [Publications] Yamamoto K,Miyagawa J,Waguri M,Hanafusa T,Matsuzawa Y. et al : "Recombinant human betacellulin promotes the neogenesis of beta-cells and ameliorates glucose intolerance in mice with diabetes induced by selective alloxan perfusion."Diabetes. 49. 2021-2027 (2000)
• [Publications] Hirano K,Matsuura F,Tsukamoto K,Matsuzawa Y et al: "Decreased expression of a member of the Rho GTPasc family, Cdc42Hs, in cells from Tangier disease-the small G protein may play a role in cholesterol efflux."FEBS Lett.. 484. 275-279 (2000)
• [Publications] Zhu Q,Yamagata K,Yu L,Tomura H,Hanafusa T,Matsuzawa Y. et al: "Identification of missense mutations in the hepatocyte nuclear factor-3beta gene in Japanese subjects with late-onset Type II diabetes mellitus."Diabetologia.. 43. 1197-1200 (2000)
• [Publications] Matsuyama A,Yamashita S,Sakai N,Hirano K,Kihara S,Matsuzawa Y et al: "Identification of a GPI-anchored type HDL-binding protein on human macrophages."Biochem Biophys Res Commun.. 272. 864-871 (2000)
• [Publications] Yokota T,Oritani K,Funahashi T,Tenner AJ,Tomiyama Y,Matsuzawa Y et al.: "Adiponectin, a novel member of soluble defense collagens, negatively regulates the growth of myelo-monocytic progenitors and the functions of macrophages."Blood. 96. 1723-1732 (2000)
• [Publications] Takahashil M,Arita Y,Yamagata K,Funahashi T,and Matsuzawa Y et al.: "Genomic structure and mutations in adipose-specific gene, adiponectin."Int.J.Obes.. 24. 861-868 (2000)
• [Publications] Hotta K,Funahashi T,Arita Y,Takahashi M,Matsuzawa Y et al.: "Plasma concentrations of a novel, adipose-specific protein, adiponectin,in type 2 diabetic patients."Arterioscler Thromb Vasc Biol.. 20. 1595-1599 (2000)
• [Publications] Okamoto Y,Arita Y,Nishida M,Funahashi T,Matsuzawa Y et al.: "An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls."Horm Metab Res.. 32. 47-50 (2000)