Chl-b down-regulates fatty acid-mediated macrophage activation and peripheral insulin resistance

• Project/Area Number: 19790179
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Environmental physiology (including Physical medicine and Nutritional physiology)
• Research Institution: The University of Tokushima
• Principal Investigator: HIRASAKA Katsuya The University of Tokushima, 大学院・ヘルスバイオサイエンス研究部, 助教 (70432747)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,690,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥390,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: マクロファージ / 飽和脂肪酸 / ユビキチンリガーゼ

Research Abstract

肥満によって脂肪組織ではマクロファージの浸潤が増加し、慢性的な軽度の炎症反応を引き起こす。これまでの我々の研究において、30週齢のユビキチンリガーゼCbl-b遺伝子欠損マウスの脂肪組織ではマクロファージの浸潤や活性化が認められ、インスリン抵抗性を引き起こすことを報告した。近年、マクロファージの活性化因子として脂肪酸が注目されている。そこで、本研究では、Cbl-bを介した、脂肪酸によるマクロファージ活性化機構について検討した。
Cbl-b遺伝子欠損マウスに飽和脂肪酸を多く含む高脂肪食を負荷し、それによるサイトカインシグナル及びインスリン抵抗性への影響を検討した結果、Cbl-b遺伝子欠損マウスにおける脂肪組織では、野生型マウスに比べてマクロファージの浸潤が早期に見られ、サイトカイン発現上昇やアディポカイン発現異常がみられた。Cbl-b遺伝子欠損マウスの血中ではMCP-1の増大が認められ、それが脂肪組織へのマクロファージ浸潤増大を引き起こしたと考えられる。さらに、長期問の高脂肪食負荷はCbl-b遺伝子欠損マウスの脂肪組織及び骨格筋におけるAktのリン酸化の減弱及び脂肪肝を引き起こした。以上の知見より、Cbl-bが飽和脂肪酸によるマクロファージ活性化に関与し、インスリン抵抗性の発症機構に寄与することが示唆された。このように、Cbl-bは食事性肥満におけるインスリン抵抗性治療の重要な分子ターゲットになりうると考えられる。

Research Products

• [Journal Article] Effects of Dimethyl Sulphoxide and Dexamethasone on mRNA Expression of Myogenesis-and Muscle Proteolytic System-related Genes in Mouse Myoblastic C2C12 Cells. (2008)
  • Author(s): Nishimura M, Mikura M, Hirasaka K, Okumura Y, Nikawa T, Kawano Y, Nakayama M, Ikeda M.
  • Journal Title: J Biochem 44(6) Pages: 717-724
  • NAID: 10024913840
  • Peer Reviewed
• [Journal Article] Cathepsin C propeptide interacts with intestinal alkaline phosphatase and heat shock cognate protein 70 in human Caco-2 cells (2008)
  • Author(s): Hirasaka K, Tokuoka K, Nakao R, Yamada C, Oarada M, Imagawa T, Ishidoh K, Okumura Y, Kishi K, Nikawa T.
  • Journal Title: J Phys Sci 58(2) Pages: 105-111
  • NAID: 10022597892
  • Peer Reviewed
• [Journal Article] Subcutaneous injection, from birth, of epigallocatechin-3-gallate, a component of green tea, limits the onset of muscular dystrophy in mdx mice : a quantitative histological, immunohistochemical and electrophysiological study. (2008)
  • Author(s): Nakae Y, Hirasaka K, Goto J, Nikawa T, Shono M, Yoshida M, Steward PJ.
  • Journal Title: Histochem Cell Biol 129(4) Pages: 489-501
  • Peer Reviewed
• [Journal Article] Effects of dietary fish oil on lipid peroxidation and serum triacylglycerol levels in psychologically stressed mice (2008)
  • Author(s): Oarada M, Tsuzuki T, Gonoi T, Igarashi M, Kamei K, Nikawa T, Hirasaka K, Ogawa T, Miyazawa T, Nakagawa K, Kurita N.
  • Journal Title: Nutrition 24(1) Pages: 67-75
  • Peer Reviewed
• [Journal Article] Preventive Effect of Isometric Contraction Exercise on Disuse Muscle Atrophy Using Tail Suspension Mice. (2008)
  • Author(s): Kawahara Y, Nikawa T, Hirasaka K, Miyashita T, Kataoka K, Yuge L.
  • Journal Title: Phys Ther Sci 20 Pages: 39-44
  • NAID: 10024158950
  • Peer Reviewed
• [Journal Article] Preventive Effect of Isometric Contraction Exercise on Disuse Muscle Atrophy Using Tail Suspension Mice (2008)
  • Author(s): Kawahara Y, et.al.
  • Journal Title: J Phys Ther Sci 20 Pages: 39-44
  • Peer Reviewed
• [Journal Article] Effects of dietary fish oil on lipid peroxidation and serum triacylglycerol levels in psychologically stressed mice (2008)
  • Author(s): Oarada M, et.al.
  • Journal Title: Nutrition 24 Pages: 67-75
  • Peer Reviewed
• [Journal Article] Subcutaneous injection, from birth, of epigallocatechin-3-gallate, a component of green tea, limits the onset of muscular dystrophy inmdx mice : a quantitative histological, immunohistochemical and electrophysiological study (2008)
  • Author(s): Nakae Y, et.al.
  • Journal Title: Histochem Cell Biol 129 Pages: 489-501
  • Peer Reviewed
• [Journal Article] Cathepsin C propeptide interacts with intestinal alkaline phosphatase and heat shock cognate protein 70 in human Caco-2 cells (2008)
  • Author(s): Hirasaka K, et.al.
  • Journal Title: J Phys Sci 58 Pages: 105-111
  • NAID: 10022597892
  • Peer Reviewed
• [Journal Article] Effects of Dimethyl Sulphoxide and Dexamethasone on mRNA Expression of Myogenesis-and Muscle Proteolytic System-related Genes in Mouse Myoblastic C2C12 Cells (2008)
  • Author(s): Nishimura M, et.al.
  • Journal Title: J Biochem 44 Pages: 717-724
  • Peer Reviewed
• [Journal Article] Osteoactivin fragments produced by ec todoma in shedding induce MMP-3 expression via ERK pathway in mouse NIH-3T3 fibroblasts (2007)
  • Author(s): Furochi H, Tamura 5, Mameoka M, Yamada C, Ogawa T, Hirasaka K, Okumura Y, Imagawa T, Oguri S, Ishidoh K, Kishi K, Higashiyama S, Nikawa T.
  • Journal Title: FEBS Lett 581(30) Pages: 6743-5750
  • Peer Reviewed
• [Journal Article] Deficiency of Cbl-b gene enhances infiltration and activation of macrophages in adipose tissue and causes peripheral insulin resistance in mice (2007)
  • Author(s): Hirasaka K, Kohno 5, Goto J, Furochi H, Mawatari K, Harada N, Hosaka T, Nakaya Y, Ishidoh K, Obata T, Ebina Y, Gu H, Takeda S, Kishi K, Nikawa T
  • Journal Title: Diabetes 56(10) Pages: 2511-2522
  • NAID: 120006324305
  • Peer Reviewed
• [Journal Article] Distinct effects of the lateral hypothalamus and anterior pyriform cortex destructions on protein intake in rats (2007)
  • Author(s): Nakao R, Ozaki E, Hasegawa M, Kondo A, Uezu K, Hirasaka K, Nikawa T, Kishi K
  • Journal Title: Pled Invest 54(3-4) Pages: 255-260
  • Peer Reviewed
• [Journal Article] Overexpression of osteoactivin protects skeletal muscle from severe degeneration caused by long-term denervation in mice (2007)
  • Author(s): Furochi H, Tamura S, Takeshima K, Hirasaka K, Nakao R, Kishi K, NikawaT
  • Journal Title: J Med Invest 54(3-4) Pages: 248-254
  • NAID: 130004822546
  • Peer Reviewed
• [Journal Article] Effects of single administration of Rokumi-gan (Tj-87) on serum amino acid concentration of 6 healthy Japanese male volunteers (2007)
  • Author(s): Takahashi H, Nakao R, Hirasaka K, Kishi K, Nikawa T
  • Journal Title: J Med Invest 54(1-2) Pages: 91-8
  • NAID: 110006215205
  • Peer Reviewed
• [Journal Article] Effect of dietary oils on lymphocyte immunological activity in psychologically stressed mice (2007)
  • Author(s): Oarada M, Gonoi T, Tsuzuki T, Igarashi M, Hirasaka K, Nikawa T, Onishi Y, Toyotome T, Kamei K, Miyazawa T, Nakagawa K, Kashima M, Kurita N
  • Journal Title: Biosci Biotechnol Biochem 71(1) Pages: 174-82
  • NAID: 10027510395
  • Peer Reviewed
• [Journal Article] Distinct expression of mast cell tryptase and protease activated receptor-2 in synovia of rheumatoid arthritis and osteoarthritis (2007)
  • Author(s): Nakano S, Mishiro T, Takahara S, Yokoi H, Hamada D, Yukata K, Takata Y, Goto T, Egawa H, Yasuoka S, Furouchi H, Hirasaka K, Nikawa T, Yasui N
  • Journal Title: Clin Rheumatol 26(8) Pages: 1284-92
  • Peer Reviewed
• [Journal Article] Deficiency of Cbl-b gene enhances infiltration and activation of macrophages in adipose tissue and causes peripheral insulin resistance in mice. (2007)
  • Author(s): Hirasaka K, et. al.
  • Journal Title: Diabetes 56 Pages: 2511-2522
  • NAID: 120006324305
  • Peer Reviewed
• [Journal Article] Distinct expression of mast cell tryptase and protease activated receptor-2 in synovia of rheumatoid arthritis and osteoarthritis (2007)
  • Author(s): Nakano S, et. al.
  • Journal Title: Clin Rheumatol 26 Pages: 1284-1292
  • Peer Reviewed
• [Journal Article] Effect of dietary oils on lymphocyte immunological activity in psychologi cally stressed mice (2007)
  • Author(s): Oarada M, et. al.
  • Journal Title: Biosci Biotechnol Biochem 71 Pages: 174-182
  • Peer Reviewed
• [Journal Article] Effects of single administration of Rokumi-gan (TJ-87) on serum amino acid concentration of 6 healthy Japanese male volunteers (2007)
  • Author(s): Takahashi H, et. al.
  • Journal Title: J Med Invest 54 Pages: 91-98
  • Peer Reviewed
• [Journal Article] Overexpression of osteoactivin protects skeletal muscle from severe dege neration caused by long-term denervation in mice (2007)
  • Author(s): Furochi H, et. al.
  • Journal Title: J Med Invest 54 Pages: 248-254
  • Peer Reviewed
• [Journal Article] Distinct effects of the lateral hypothalamus and anterior pyriform cortex destructions on protein intake in rats (2007)
  • Author(s): Nakao R, et. al.
  • Journal Title: J Med Invest 54 Pages: 255-260
  • Peer Reviewed
• [Journal Article] Osteoactivin fragments produced by ectodomain shedding induce MMP-3 expression via ERK pathway in mouse NIH-3T3 fibroblasts (2007)
  • Author(s): Furochi H, et. al.
  • Journal Title: FEBS Lett 581 Pages: 5743-5750
  • Peer Reviewed
• [Presentation] 微小重力環境下での筋萎縮に対するポリフェノールの阻害効果 (2008)
  • Author(s): 平坂勝也、Dalia Hemdan、加川祥子、河野尚平、中尾玲子、原田晃子、奥村裕司、二川健
  • Organizer: 第22回日本宇宙生物科学会
  • Place of Presentation: 奈良
  • Year and Date: 2008-10-26
• [Presentation] Ubiquitin ligase, MuRF-1 regulates myosin heavy chain type Iia transcripts during muscle atrophy under microgravity conditions (2008)
  • Author(s): Kagawa S, Hirasaka K, Kohno 5, Okumura Y, Nikawa T
  • Organizer: 37th COSPAR Scientific Assembly
  • Place of Presentation: Canada, Montreal
  • Year and Date: 2008-07-18
• [Presentation] Ubiquitin ligase, MuRF-1 regulates myosin heavy chain type IIa transcripts during muscle atrophy under microgravity conditions (2008)
  • Author(s): Kagawa S, et.al.
  • Organizer: 37th COSPAR Scientific Assembly
  • Place of Presentation: モントリオールCanada
  • Year and Date: 2008-07-18
• [Presentation] 飽和脂肪酸によるCb1-bを介したマクロファージの活性化のメカニズム (2008)
  • Author(s): 平坂勝也、加川祥子、河野尚平、中尾玲子、助野晃子、奥村裕司、二川健
  • Organizer: 第62回日本栄養・食糧学会
  • Place of Presentation: 埼玉
  • Year and Date: 2008-05-03
• [Presentation] Cbl-bを介したマクロファージ活性化制御機構 (2007)
  • Author(s): 加川祥子、平坂勝也、河野尚平、藤倉由浮都、中尾玲子、二川健
  • Organizer: 日本栄養・食糧学会中四国支部会
  • Place of Presentation: 広島
  • Year and Date: 2007-11-17
• [Presentation] Deficiency of Cbl-b gene enhances infiltration and activation of macrophages in adipose tissue and causes peripheral insulin resistance in mice (2007)
  • Author(s): Shohei Kohno, Katsuya Hirasaka, Momoko Ogawa, Sachiko Kagawa, jumpei Goto, Ilarumi Furochi, Kazumi Ishidoh, Takeshi Nikawa
  • Organizer: General Meeting of the International Proteolysis Society
  • Place of Presentation: Patras, Greece
  • Year and Date: 2007-10-27
• [Presentation] Cb1-b欠損によるマクロファージの活性化とインスリン抵抗性 (2007)
  • Author(s): 平坂勝也、河野尚平、阿部愛波、上西千晶、岸恭一、二川健
  • Organizer: 第61回日本栄養・食糧学会
  • Place of Presentation: 京都
  • Year and Date: 2007-05-19
• [Presentation] Cbl-b欠損によるマクロファージの活性化とインスリン抵抗性 (2007)
  • Author(s): 平坂勝也
  • Organizer: 日本栄養・食糧学会
  • Place of Presentation: 京都
  • Year and Date: 2007-05-19
• [Remarks] 学会賞受賞をホームページで公開
  • URL: http://www.hosp.med.tokushima-u.ac.jp/university/servlet/index?&level=4&reference=0/10002/5/30010/20032