Pro-inflammatory role of free fatty acids in the pathophysiology of the metabolic syndrome

• Project/Area Number: 18689022
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Endocrinology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: SUGAMI Takayoshi Tokyo Medical and Dental University, 難治疾患研究所, 助教 (50343752)
• Research Collaborator: YOSHIDA Masayuki 東京医科歯科大学, 医歯学総合研究科, 教授 (80282771) ; YOSHIMASA Yasunao 国立循環器病センター, 部長 (00252437) ; SATO Noriko 京都医療センター, 室長 (80373512)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥27,300,000 (Direct Cost: ¥21,000,000、Indirect Cost: ¥6,300,000); Fiscal Year 2008: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2007: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000); Fiscal Year 2006: ¥12,740,000 (Direct Cost: ¥9,800,000、Indirect Cost: ¥2,940,000)
• Keywords: 脂肪酸 / 肥満 / 脂肪細胞 / マクロファージ / 炎症 / メタボリックシンドローム / 飽和脂肪酸 / 多価不飽和脂肪酸 / Toll-like receptor 4

Research Abstract

肥満の脂肪組織から遊離する飽和脂肪酸が、生体の自然免疫反応に重要な4型Toll様受容体を介してマクロファージを活性化し、脂肪組織の炎症性変化や全身の糖代謝を制御することを証明した。本研究成果により、飽和脂肪酸がメタボリックシンドロームの基盤病態である内臓脂肪の蓄積と全身の慢性炎症、すなわち、代謝と炎症を繋ぐ鍵分子であることを明らかにした。

Research Products

• [Journal Article] Role of C-C chemokine receptor 2 in bone marrow cells in the recruitment of macrophages into obese adipose tissue (2008)
  • Author(s): A. Ito, T. Suganami, A. Yamauchi, M. Degawa-Yamauchi, M. Tanaka, R. Kouyama, Y. Kobayashi, N. Nitta, K. Yasuda, Y. Hirata, WA. Kuziel, M. Takeya, S. Kanegasaki, Y. Kamei, Y. Ogawa
  • Journal Title: J. Biol. Chem. 283 Pages: 35715-35723
  • Peer Reviewed
• [Journal Article] In vivo and in vitro inhibition of monocyte adhesion to endothelial cells and endothelial adhesion molecules by eicosapentaenoic acid (2008)
  • Author(s): H. Yamada, M. Yoshida, Y. Nakano, T. Suganami, N. Satoh, T Mita, K. Azuma, M. Itoh, Y. Yamamoto, Y. Kamei, M. Horie, H. Watada, Y. Ogawa
  • Journal Title: Arterioscler. Thromb. Vase. Biol. 28 Pages: 2173-2179
  • Peer Reviewed
• [Journal Article] Regulation of SREBP1c gene expression in skeletal muscle: role of RXR/LXR and FOX01 (2008)
  • Author(s): Y. Kamei, S. Miura, T Suganami, F. Akaike, S. Kanai, S. Sugita, A. Katsumata, H. Aburatani, TG. Unterman, O. Ezaki, Y. Ogawa
  • Journal Title: Endocrinology 149 Pages: 293-2305
  • Peer Reviewed
• [Journal Article] Effect of peroxisome proliferator-activated receptor a ligands in the interaction between adipocytes and macrophages in obese adipose tissue (2008)
  • Author(s): T. Toyoda, Y. Kamei, H. Kato, S. Sugita, M. Takeya, T. Suganami, Y. Ogawa
  • Journal Title: Obesity 16 Pages: 1199-1207
  • Peer Reviewed
• [Journal Article] Role of C-C chemokine receptor 2 in bone marrow cells in the recruitment of macrophages into obese adipose tissue (2008)
  • Author(s): A.Ito, et.al.
  • Journal Title: J.Biol.Chem 283 Pages: 35715-35723
  • Peer Reviewed
• [Journal Article] In vivo and in vitro inhibition of monocyte adhesion to endothelial cells and endothelial adhesion molecules by eicosapentaenoic acid (2008)
  • Author(s): H.Yamada, et.al.
  • Journal Title: Arterioscler. Thromb. Vasc. Biol 28 Pages: 173-2179
  • Peer Reviewed
• [Journal Article] Effect of peroxisome proliferator-activated receptor α ligands in the interaction between adipocytes and macrophages in obese adipose tissue (2008)
  • Author(s): T.Toyoda, et.al.
  • Journal Title: Obesity 16 Pages: 1199-1207
  • Peer Reviewed
• [Journal Article] Regulation of SREBPlc gene expression in skeletal muscle : role of RXR/LXR and FOXO1 (2008)
  • Author(s): Y.Kamei, et.al.
  • Journal Title: Endocrinology 149 Pages: 2293-2305
  • Peer Reviewed
• [Journal Article] Effect of peroxisome proliferator-activated receptor α ligands in the interaction between adipocytes and macrophages in obese adipose tissue. (2008)
  • Author(s): T. Toyoda et. al.
  • Journal Title: Obesity (印刷中)
  • Peer Reviewed
• [Journal Article] Role of the Toll-like receptor 4/NF-κB pathway in saturated fatty acid-induced inflammatory change in the interaction between adipocytes and macrophages (2007)
  • Author(s): T. Suganami, K. Tammoto-Koyama, J. Nishida, M. Itoh, X. Yuan, S. Mizuarai, H. Kotani, S. Yamaoka, K. Miyake, S. Aoe, Y. Kamei, Y. Ogawa
  • Journal Title: Arterioscler. Thromb. Vase. Biol. 27 Pages: 84-91
  • Peer Reviewed
• [Journal Article] Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-Iike receptor 4mutation (2007)
  • Author(s): T. Suganami, T. Mieda, M. Itoh, Y. Shimoda, Y. Kamei, Y. Ogawa
  • Journal Title: Biochem. Biophys. Res. Commun. 354 Pages: 45-49
  • Peer Reviewed
• [Journal Article] Purified eicosapentaenoic acid reduces small dense LDL, remnant lipoprotein particles, and CRP in metabolic syndrome (2007)
  • Author(s): N. Satoh, A. Shimatsu, K. Kotani, N. Sakane, K. Yamada, T. Suganami, H. Kuzuya, Y. Ogawa
  • Journal Title: Diabetes Care 30 Pages: 144-146
  • Peer Reviewed
• [Journal Article] Pegl/Mest in obese adipose tissue is expressed from the paternal allele in an isoform-specific manner (2007)
  • Author(s): Y. Kamei, T. Suganami, T. Kohda, F. Ishino, K. Yasuda, S. Miura, O. Ezaki, Y. Ogawa
  • Journal Title: FEBS Letters 581 Pages: 91-96
  • Peer Reviewed
• [Journal Article] Increased adiponectin secretion by highly purified eicosapentaenoic acid in rodent models of obesity and human obese subjects (2007)
  • Author(s): M. Itoh, T. Suganami (co-corresponding author), N. Satoh, K. Tanimoto-Koyama, X. Yuan, M. Tanaka, H. Kawano, T. Yano, S. Aoe, M. Takeya, A. Shimatsu, H. Kuzuya, Y. Kamei, Y. Ogawa
  • Journal Title: Arterioscler. Thromb. Vase. Biol. 27 Pages: 1918-1925
  • Peer Reviewed
• [Journal Article] Role of MAPK phosphatase-1 in the induction of monocyte chemoattractant protein-1 during the course of adipocyte hypertrophy (2007)
  • Author(s): A. Ito, T. Suganami, Y. Miyamoto, Y. Yoshimasa, M. Takeya, Y. Kamei, Y. Ogawa
  • Journal Title: J. Biol. Chem. 282 Pages: 15445-25452
  • Peer Reviewed
• [Journal Article] Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development (2007)
  • Author(s): R. Hachiya, Y. Ohashi, Y. Kamei, T. Suganami, H. Mochizuki, N. Mitsui, M. Saitoh, M. Sakuragi, G. Nishimura, H. Ohashi, T. Hasegawa, Y. Ogawa
  • Journal Title: J. Clin. Endocrinol. Metab. 92 Pages: 4009-4014
  • Peer Reviewed
• [Journal Article] Macrophage-colony stimulating factor in obese adipose tissue: studies with heterozygous op/+ mice (2007)
  • Author(s): S. Sugita, Y. Kamei, J. Oka, T. Suganami, Y. Ogawa
  • Journal Title: Obesity 15 Pages: 1988-1995
  • Peer Reviewed
• [Journal Article] メタボリックシンドロームと脂肪細胞 (2007)
  • Author(s): 菅波孝祥、小川佳宏
  • Journal Title: 内分泌・糖尿病科 24 Pages: 433-440
• [Journal Article] Increased adiponectin secretion by highly purified eicosapentaenoic acid in rodent models of obesity and human obese subjects. (2007)
  • Author(s): M. Itoh et. al.
  • Journal Title: Arterioscler. Thromb. Vasc. Biol. 27 Pages: 1918-1925
  • Peer Reviewed
• [Journal Article] Role of MAPK phosphatase-1 in the induction of monocyte chemoattractant protein-1 during the course of adipocyte hypertrophy. (2007)
  • Author(s): A. Ito et. al.
  • Journal Title: J. Biol. Chem. 282 Pages: 25445-25452
  • Peer Reviewed
• [Journal Article] Macrophage-colony stimulating factor in obese adipose tissue: studies with heterozygous op/+ mice. (2007)
  • Author(s): S. Sugita et. al.
  • Journal Title: Obesity 15 Pages: 1988-1995
  • Peer Reviewed
• [Journal Article] Role of the toll-like receptor 4/NF-κB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. (2007)
  • Author(s): T.Suganami et al.
  • Journal Title: Arterioscler. Thromb. Vasc. Biol. 27 Pages: 84-91
• [Journal Article] Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation. (2007)
  • Author(s): T.Suganami et al.
  • Journal Title: Biochem. Biophys. Res. Commun. 354 Pages: 45-49
• [Journal Article] Purified eicosapentaenoic acid reduces small dense LDL, remnant lipoprotein particles, and CRP in metabolic syndrome. (2007)
  • Author(s): N.Satoh et al.
  • Journal Title: Diabetes Care 30 Pages: 144-146
• [Journal Article] An α-glucosidase inhibitor voglibose reduces oxidative stress markers and soluble intercellular adhesion molecule-1 in obese type 2 diabetes (2006)
  • Author(s): N. Satoh, A. Shimatsu, K. Yamada, M. Aizawa-Abe, T. Suganami, H. Kuzuya, Y. Ogawa
  • Journal Title: Metabolism 55 Pages: 786-793
  • Peer Reviewed
• [Journal Article] Increase in glucose-6-phosphate dehydrogenase in adipocytes stimulates oxidative stress and inflammatory signals (2006)
  • Author(s): J. Park, SS. Choe, AH. Choi, KH. Kim, MJ. Yoon, T. Suganami, Y. Ogawa, JB. Klm
  • Journal Title: Diabetes 55 Pages: 2939-2949
  • Peer Reviewed
• [Journal Article] 脂肪組織の量的質的変化と糖尿病 (2006)
  • Author(s): 菅波孝祥, 小川佳宏
  • Journal Title: BIO Clinica 21 Pages: 42-47
• [Journal Article] メタボリックシンドロームの鍵分子 (2006)
  • Author(s): 菅波孝祥, 小川佳宏
  • Journal Title: レプチン循環器科 59 Pages: 152-159
• [Journal Article] 肥満の脂肪組織における脂肪細胞とマクロファージのパラクリン調節系-共培養系を用いた検討- (2006)
  • Author(s): 菅波孝祥, 亀井康富, 小川佳宏
  • Journal Title: 肥満研究 12 Pages: 70-72
  • NAID: 10026149038
• [Journal Article] 肥満と脂肪組織の炎症性変化 (2006)
  • Author(s): 菅波孝祥, 小川佳宏
  • Journal Title: 分子細胞治療 5 Pages: 51-56
• [Journal Article] 脂肪組織内マクロファージの機能 (2006)
  • Author(s): 菅波孝祥, 小川佳宏
  • Journal Title: アディポサイエンス 3 Pages: 139-147
• [Journal Article] 脂肪組織へのマクロファージ浸潤とその意義 (2006)
  • Author(s): 菅波孝祥、小川佳宏
  • Journal Title: 日本臨床 (増刊号9)64 Pages: 198-202
• [Journal Article] Increase in glucose-6-phosphate dehydrogenase in adipocytes stimulates oxidative stress and inflammatory signals. (2006)
  • Author(s): J.Park et al.
  • Journal Title: Diabetes 55 Pages: 2939-2949
• [Journal Article] An a-glucosidase inhibitor voglibose reduces oxidative stress markers and soluble intercellular adhesion molecule-1 in obese type 2 diabetes. (2006)
  • Author(s): N.Satoh et al.
  • Journal Title: Metabolism 55 Pages: 786-793
• [Journal Article] The neuro-protective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential. (2006)
  • Author(s): K.Miyashita et al.
  • Journal Title: Endocrinology 147 Pages: 1642-1653
• [Presentation] 脂肪組織リモデリング (2008)
  • Author(s): 菅波孝祥、小川佳宏
  • Organizer: シンポジウム「メタボリックシンドローム」, 日本実験動物科学技術2008
  • Place of Presentation: 仙台
• [Presentation] 肥満脂肪組織における脂肪細胞とマクロファージの相互作用 (2008)
  • Author(s): 菅波孝祥、小川佳宏
  • Organizer: シンポジウム「肥満脂肪細胞の病態」, 第29回日本肥満学会学術大会
  • Place of Presentation: 大分
• [Presentation] 肥満脂肪組織における脂肪細胞とマクロファージの相互作用 (2008)
  • Author(s): 菅波孝祥, 他
  • Organizer: 第29回日本肥満学会学術大会
  • Place of Presentation: 大分
• [Presentation] 脂肪組織リモデリング (2008)
  • Author(s): 菅波孝祥, 他
  • Organizer: 日本実験動物科学技術2008
  • Place of Presentation: 仙台
• [Presentation] 腎障害進展における中枢神経系を介した臓器間クロストークの病態生理的意義の解明 (2007)
  • Author(s): 菅波孝祥
  • Organizer: CKD Award
  • Place of Presentation: 東京
  • Year and Date: 2007-11-17
• [Presentation] 脂肪組織リモデリングの分子機構と病態生理的意義 (2007)
  • Author(s): 菅波孝祥、小川佳宏
  • Organizer: 第12回アディポサイエンス研究会
  • Place of Presentation: 大阪
  • Year and Date: 2007-08-18
• [Presentation] Role of the Toll-like Receptor 4/NF-kB Pathway in Saturated Fatty Acid-induced Inflammatory Changes in the Interaction between Adipocytes and Macrophages (2007)
  • Author(s): T. Suganami, Y. Ogawa
  • Organizer: Keystone Symposia
  • Place of Presentation: Steamboat Springs, USA
• [Presentation] 肥満の脂肪組織炎症におけるTLR4の病態生理的意義 (2007)
  • Author(s): 菅波孝祥、伊藤美智子、小川佳宏
  • Organizer: 第80回日本内分泌学会学術総会
  • Place of Presentation: 東京
• [Presentation] メタボリックシンドロームとマクロファージ機能 (2007)
  • Author(s): 菅波孝祥、小川佳宏
  • Organizer: シンポジウム「肥満症、メタボリックシンドロームと血管、炎症、血栓」, 第28回日本肥満学会学術大会
  • Place of Presentation: 東京
• [Presentation] メタボリックシンドロームとマクロファージ機能 (2007)
  • Author(s): 菅波孝祥, 他
  • Organizer: 第28回日本肥満学会学術大会
  • Place of Presentation: 東京
• [Presentation] Aparacrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor-α (2006)
  • Author(s): T. Suganami, Y. Kamei, Y. Ogawa
  • Organizer: Keystone Symposia
  • Place of Presentation: Vancouver, Canada
• [Presentation] アディポサイトカイン産生調節の破綻 : 脂肪細胞とマクロファージが構成するパラクリン調節系の意義 (2006)
  • Author(s): 菅波孝祥、小川佳宏
  • Organizer: メインシンポジウム「メタポリックシンドロームとadipocytokines」, 第79回日本内分泌学会学術総会
  • Place of Presentation: 神戸
• [Presentation] 脂肪細胞・マクロファージ相互作用の分子機構の検討-TLR4/NF-kB系の役割について- (2006)
  • Author(s): 菅波孝祥、小山佳奈美、西田淳子、伊藤美智子、袁勲梅、青江誠一郎、亀井康富、小川佳宏
  • Organizer: 第27回日本肥満学会学術大会
  • Place of Presentation: 神戸
• [Book] カラー版 糖尿病学 基礎と臨床, レプチンシグナル
  • Author(s): 菅波孝祥、田中都、小川佳宏
  • Publisher: 西村書店
• [Book] 新時代の糖尿病学, レプチンとレプチン受容体
  • Author(s): 菅波孝祥、田中都、小川佳宏
  • Publisher: 日本臨床
• [Remarks]
  • URL: http://www.tmd.ac.jp/mri/prm/index.html
• [Remarks]
  • URL: http://www.tmd.ac.jp/mri/prm/index.html
• [Remarks]
  • URL: http://www.tmd.ac.jp/mri/prm/index.html
• [Patent(Industrial Property Rights)] 脂肪細胞の炎症性変化を効果的に抑制する物質をスクリーニングするためのスクリーニング系及びそれを用いたスクリーニング方法 (2007)
  • Inventor(s): 小川佳宏、菅波孝祥
  • Industrial Property Rights Holder: 国立大学法人東京医科歯科大学
  • Filing Date: 2007-09-28
• [Patent(Industrial Property Rights)] 脂肪細胞の炎症性変化を抑制する物質のスクリーニング系及びそれを用いたスクリーニング方法 (2007)
  • Inventor(s): 小川佳宏、菅波孝祥
  • Industrial Property Rights Holder: 国立大学法人東京医科歯科大学
  • Industrial Property Number: 2007-528129
  • Filing Date: 2007-09-28