Involvement of pericytes-derived cyclophilin A in the development of insulin resistanse in the brain

• Project/Area Number: 23790113
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Fukuoka University
• Principal Investigator: TAKATA Fuyuko 福岡大学, 薬学部, 助教 (70412575)
• Research Collaborator: KATAOKA Yasufumi 福岡大学, 薬学部, 教授 (70136513) ; DOHGU Shinya 福岡大学, 薬学部, 准教授 (60399186) ; MATSUMOTO Junichi 福岡大学, 薬学部, 助教 (10550064) ; MACHIDA Takashi 福岡大学, 薬学部, 助教 (30586144)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 脳ペリサイト / cyclophilin A / 脳インスリン抵抗性 / ペリサイト / GT1-7 / インスリン抵抗性 / シクロフィリンA / 糖尿病 / メチルグリオキサール / 脂質ラフト / 視床下部神経 / シクロフィリンＡ

Research Abstract

Brain pericytes in the microvasculature are periendothelial accessory structures of the blood-brain barrier (BBB). We previously demonstrated that pericytes increase insulin sensitivity in the hypothalamic neurons through soluble factors under the physiological conditions. However, under the pathological conditions such as diabetes mellitus (DM), a role of pericytes in hypothalamic insulin sensitivity remained obscure. The expression of cyclophilin A (CypA) and its receptor, CD147 in the brain and brain microvessels were increased in the obese mice with impaired glucose tolerance induced by high fat diet. CypA release from pericytes was much higher than that from other BBB-constituting cells under the physiological conditions. TNF-a increased CypA release from pericytes. The treatment of TNF-a combined with CypA decreased insulin sensitivity in the hypothalamic neurons. Therefore, pericytes and pericytal CypA could be involved in insulin resistance in the central nervous system.

Research Products

• [Journal Article] Metformin induces up-regulation of blood-brain barrier functions by activating AMP-activated protein kinase in rat brain microvascular endothelial cells (2013)
  • Author(s): Takata F, Dohgu S, Matsumoto J, Machida T, Kaneshima S, Matsuo M, Sakaguchi S, Takeshige Y, Yamauchi A, Kataoka Y
  • Journal Title: Biochem Biophys Res Commun Volume: 19,433(4) Pages: 586-90
  • DOI: 10.1016/j.bbrc.2013.03.036.
  • Peer Reviewed
• [Journal Article] Paracellular barrier and tight junction protein expression in the immortalized brain endothelial cell lines bEND.3, bEND.5 and mouse brain endothelial cell 4 (2013)
  • Author(s): Watanabe T, Dohgu S, Takata F, Nishioku T, Nakashima A, Futagami K, Yamauchi A, Kataoka Y
  • Journal Title: Biol Pharm Bull Volume: 36(3) Pages: 492-5
  • Peer Reviewed
• [Journal Article] In vitro blood-brain barrier models using brain capillary endothelial cells isolated from neonatal and adult rats retain age-related barrier properties (2013)
  • Author(s): Takata F, Dohgu S, Yamauchi A, Matsumoto J, Machida T, Fujishita K, Shibata K, Shinozaki Y, Sato K, Kataoka Y, Koizumi S
  • Journal Title: PLoS One Volume: 8(1) Pages: 55166
  • DOI: 10.1371/journal.pone.0055166.
  • Peer Reviewed
• [Journal Article] Metformin induces up-regulation of blood-brain barrier functions by activating AMP-activated protein kinase in rat brain microvascular endothelial cells. (2013)
  • Author(s): Takata F, Dohgu S, Matsumoto J, Machida T, Kaneshima S, Matsuo M, Sakaguchi S, Takeshige Y, Yamauchi A, Kataoka Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 19; 433(4) Pages: 586-590
  • DOI: 10.1016/j.bbrc.2013.03.036.
  • Peer Reviewed
• [Journal Article] Paracellular barrier and tight junction protein expression in the immortalized brain endothelial cell lines bEND.3, bEND.5 and mouse brain endothelial cell 4. (2013)
  • Author(s): Watanabe T, Dohgu S, Takata F, Nishioku T, Nakashima A, Futagami K, Yamauchi A, Kataoka Y.
  • Journal Title: Biol Pharm Bull. Volume: 36(3) Pages: 492-495.
  • Peer Reviewed
• [Journal Article] In vitro blood-brain barrier models using brain capillary endothelial cells isolated from neonatal and adult rats retain age-related barrier properties. (2013)
  • Author(s): Takata F, Dohgu S, Yamauchi A, Matsumoto J, Machida T, Fujishita K, Shibata K, Shinozaki Y, Sato K, Kataoka Y, Koizumi S.
  • Journal Title: PLoS One. Volume: 8(1) Pages: e55166
  • DOI: 10.1371/journal.pone.0055166.
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide-activated microglia lower P-glycoprotein function in brain microvascular endothelial cells (2012)
  • Author(s): Matsumoto J, Dohgu S, Takata F, Nishioku T, Sumi N, Machida T, Takahashi H, Yamauchi A, Kataoka Y
  • Journal Title: Neurosci Lett Volume: 22,524(1) Pages: 45-8
  • DOI: 10.1016/j.neulet.2012.07.004.
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide-activated microglia lower P-glycoprotein function in brain microvascular endothelial cells. (2012)
  • Author(s): Matsumoto J, Dohgu S, Takata F, Nishioku T, Sumi N, Machida T, Takahashi H, Yamauchi A, Kataoka Y.
  • Journal Title: Neurosci Lett. Volume: 524(1) Pages: 45-48
  • DOI: 10.1016/j.neulet.2012.07.004.
  • Peer Reviewed
• [Journal Article] Brain pericytes among cells constituting the blood-brain barrier are highly sensitive to tumor necrosis factor-α, releasing matrix metalloproteinase-9 and migrating in vitro (2011)
  • Author(s): Takata F, Dohgu S, Matsumoto J, Takahashi H, Machida T, Wakigawa T, Harada E, Miyaji H, Koga M, Nishioku T, Yamauchi A, Kataoka Y
  • Journal Title: J Neuroinflammation Volume: 26 Pages: 106
  • DOI: 10.1186/1742-2094-8-106
  • Peer Reviewed
• [Journal Article] Brain pericytes among cells constituting the blood-brain barrier are highly sensitive to tumor necrosis factor-alpha, releasing matrix metalloproteinase-9 and migrating in vitro. (2011)
  • Author(s): Takata F, Dohgu S, Matsumoto J, Takahashi H, Machida T, Wakigawa T, Harada E, Miyaji H, Koga M, Nishioku T, Yamauchi A, Kataoka Y.
  • Journal Title: J Neuroinflammation. Volume: 26：8 Pages: 106
  • DOI: 10.1186/1742-2094-8-106
  • Peer Reviewed
• [Presentation] メトホルミンによる血液脳関門機能強化 (2013)
  • Author(s): 高田芙友子、道具伸也、松本純一、町田崇、山内淳史、片岡泰文
  • Organizer: 第15回応用薬理シンポジウム
  • Place of Presentation: コクヨホール
  • Year and Date: 20130928-29
• [Presentation] 脳ペリサイト由来液性因子による血液脳関門障害 (2013)
  • Author(s): 道具伸也、高田芙友子、松本純一、町田崇、高橋弘之、山内淳史、片岡泰文
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 20130321-23
• [Presentation] 乳幼児と成人期の血液脳関門in vitroモデル (2012)
  • Author(s): 高田芙友子
  • Organizer: 第１４回応用薬理シンポジウム
  • Place of Presentation: ベルクラシック甲府
  • Year and Date: 20120903-20120904
• [Presentation] 乳幼児と成人期の血液脳関門in vitroモデル (2012)
  • Author(s): 高田芙友子
  • Organizer: 第14回応用薬理シンポジウム
  • Place of Presentation: ベルクラシック甲府
  • Year and Date: 20120903-04
• [Presentation] 脳ペリサイトは血液脳関門構成細胞のなかで最大のTNF-α誘発性MMP-9産生能と細胞遊走能を有する (2012)
  • Author(s): 高田芙友子、道具伸也、松本純一、町田崇、高橋弘之、山内淳史、片岡泰文
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2012-03-16
• [Presentation] 脳ペリサイトはマクロファージの脳実質内浸潤を阻害する (2012)
  • Author(s): 道具伸也、高田芙友子、松本純一、高橋弘之、町田崇、一木奈津子、関菜摘子、山内淳史、片岡泰文
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2012-03-16
• [Presentation] 脳ペリサイトに特異的なTNF-α誘発性MMP-9産生における活性酸素種およびERK1/2・Aktの遅延的活性化の関与 (2012)
  • Author(s): 町田崇、道具伸也、高田芙友子、松本純一、高橋弘之、宮地晴樹、園木優唯、山内淳史、片岡泰文
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2012-03-16
• [Presentation] 脳ペリサイトのIL-6放出機構 (2011)
  • Author(s): 松本純一、道具伸也、高田芙友子、堂籠航、川口真奈美、山内淳史、片岡泰文
  • Organizer: 第64回日本薬理学会西南部会
  • Place of Presentation: KKRホテル博多
  • Year and Date: 2011-11-20
• [Patent(Industrial Property Rights)] 血液脳関門障害症候群治療薬 (2011)
  • Inventor(s): 高田芙友子、道具伸也、片岡泰文、松本純一、金嶋修司
  • Industrial Property Rights Holder: 福岡大学
  • Industrial Property Rights Type: PCT国際
  • Industrial Property Number: PCT/JP2011/079266
  • Filing Date: 2011-12-12
  • Overseas
• [Patent(Industrial Property Rights)] 血液脳関門障害症候群治療薬 (2011)
  • Inventor(s): 高田芙友子、道具伸也、片岡泰文、松本純一、金嶋修司
  • Industrial Property Rights Holder: 福岡大学
  • Industrial Property Number: 特許: PCT/JP2011/079266
  • Filing Date: 2011年12月12日
  • Overseas