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チャネル代謝における意義-

• Project/Area Number: 13137206
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• 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 (木原 進土) 大阪大学, 医学系研究科, 助手 (20332736)
• Project Period (FY): 2001 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥35,500,000 (Direct Cost: ¥35,500,000); Fiscal Year 2004: ¥9,000,000 (Direct Cost: ¥9,000,000); Fiscal Year 2003: ¥9,000,000 (Direct Cost: ¥9,000,000); Fiscal Year 2002: ¥8,500,000 (Direct Cost: ¥8,500,000); Fiscal Year 2001: ¥9,000,000 (Direct Cost: ¥9,000,000)
• Keywords: 内臓脂肪 / aquaporin adipose / glycerol / insulin resistance

Research Abstract

Aquapoin(AQP}は生物界に広く存在する水チャネルで、細胞内外の浸透圧調節に重要である。AQPファミリーは、水透過能のみを有する狭義のAQPと、グリセロール透過能を併せ持つaquaglyceroporin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、脂肪組織特異的な発現の調節機構、グリセロール産生と連動する発現調節機構、肝臓のグリセロールチャネルとの代謝連関や、遺伝子解析によって見い出された本分子の機能欠損型ヒト変異の形質を次々と明らかにしてきた。最終年度は、本分子を一義的に欠損するノックアウトマウスを樹立、解析し、グリセロールチャネルがないことによって生体にどのような変化、異常がもたらせれるかを検討した。ノックアウトマウスは、遊離脂肪酸濃度は正常であったが、血漿グリセロール濃度が低下しており、脂肪細胞内のグリセロール含量は増加していた。β3agonist投与によるグリセロール上昇も障害されていた。空腹時血糖はやや低下していたが、インスリン感受性や筋肉、肝臓のインスリンシグナル伝達は正常であった。絶食に対し速やかに低血糖が誘発された。グルカゴン、コルチコステロン等の糖新生ホルモンが上昇しており、肝臓の糖新生系酵素発現はむしろ亢進していた。つまり糖新生基質としてのグリセロール供給低下が、低血糖をもたらしたと考えられた。ほ乳動物において、グリセロールの効率的な細胞内外透過にチャネル分子が必要であること、及びその存在が生命機能維持のために必須であることを世界で初めて明らかにした。

Research Products

• [Journal Article] Adaptation to fasting by glycerol transport through aquaporin 7 in adipose tissue. (2004)
  • Author(s): Maeda N, Funahashi T, et al.
  • Journal Title: Proc Natl Acad Sci U S A. 101 Pages: 17801-17806
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• [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)