The role of TLR9 in the development of insulin resistance

• Project/Area Number: 25460369
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: The University of Tokushima
• Principal Investigator: FUKUDA Daiju 徳島大学, 大学院医歯薬学研究部, 特任講師 (40637568)
• Co-Investigator(Kenkyū-buntansha): SATA Masataka 徳島大学, 大学院医歯薬学研究部, 教授 (80345214)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 炎症 / マクロファージ / インスリン抵抗性 / ＴＬＲ９ / 肥満 / 脂肪

Outline of Final Research Achievements

Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains obscure. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed higher plasma cfDNA levels. cfDNA released from degenerated adipocytes promoted MCP-1expression in wild-type macrophages, but not in TLR9-deficient macrophages. In fat-fed wild-type mice, genetic deletion of Tlr9 or administration of a specific TLR9 antagonist demonstrated reduced adipose tissue inflammation and better insulin sensitivity compared with the control mice. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.

Research Products

• [Journal Article] Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue (2016)
  • Author(s): Nishimoto S, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Murata C, Kim-Kaneyama JR, Sato F, Bando M, Yagi S, Soeki T, Hayashi T, Imoto I, Sakaue H, Shimabukuro M, Sata M.
  • Journal Title: Sci Adv. Volume: 2(3) Issue: 3
  • DOI: 10.1126/sciadv.1501332
  • Peer Reviewed / Open Access
• [Journal Article] Dipeptidyl Peptidase-4 Inhibitor, Linagliptin, Ameliorates Endothelial Dysfunction and Atherogenesis in Normoglycemic Apolipoprotein-E Deficient Mice. (2016)
  • Author(s): Salim HM, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Soeki T, Shimabukuro M, Sata M.
  • Journal Title: Vascul Pharmacol Volume: 79 Pages: 16-23
  • DOI: 10.1016/j.vph.2015.08.011
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Expression of NLRP3 in subcutaneous adipose tissue is associated with coronary atherosclerosis. (2015)
  • Author(s): Bando S, Fukuda D, Soeki T, Nishimoto S, Uematsu E, Matsuura T, Ise T, Tobiume T, Yamaguchi K, Yagi S, Iwase T, Yamada H, Wakatsuki T, Shimabukuro M, Sata M
  • Journal Title: Atherosclerosis Volume: 242 Issue: 2 Pages: 407-414
  • DOI: 10.1016/j.atherosclerosis.2015.07.043
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice. (2015)
  • Author(s): Hara T, Fukuda D, Tanaka K, Higashikuni Y, Hirata Y, Yagi S, Yamada H, Soeki T, Wakatsuki T, Shimabukuro M, Sata M.
  • Journal Title: Atherosclerosis. Volume: 印刷中 Issue: 2 Pages: 639-646
  • DOI: 10.1016/j.atherosclerosis.2015.03.023
  • Peer Reviewed / Open Access
• [Presentation] Critical Role in Bone Marrow Protease-Activated Receptor-2 in the Pathogenesis of Vascular Inflammation and Atherosclerosis in ApoE-Deficient Mice (2016)
  • Author(s): Hara T, Fukuda D, Tanaka K, Higashikuni Y, Hirata Y, Yagi S, Soeki T, Shimabukuro M, Sata M.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター(宮城県仙台市）
  • Year and Date: 2016-03-18
• [Presentation] Deletion of Toll-Like Receptor 9 Prevented Atherosclerosis Induced by Angiotensin II (2016)
  • Author(s): Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Soeki T, Shimabukuro M, Sata M.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター(宮城県仙台市）
  • Year and Date: 2016-03-18
• [Presentation] Linagliptin, a Dipeptidyl Peptidase-4 Inhibitor, Ameliorates Endothelial Dysfunction and Atherogenesis in Normoglycemic Apolipoprotein-E Deficient Mice through GLP-1 Dependent Manner. (2016)
  • Author(s): Salim HM, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Soeki T, Shimabukuro M, Sata M.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター(宮城県仙台市）
  • Year and Date: 2016-03-18
• [Presentation] Reduced Ratio of Eicosapentaenoic Acid and Docosahexaenoic Acid to Arachidonic Acid is Associated with Early Onset of Acute Coronary Syndrome. (2016)
  • Author(s): Yagi S, Aihara K, Fukuda D, Takashima A, Bando M, Hara T, Ise T, Kusunose K, Yamaguchi K, Tobiume T, Yamada H, Soeki T, Wakatsuki T, Shimabukuro M, Akaike M, Sata M
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター(宮城県仙台市）
  • Year and Date: 2016-03-18
• [Presentation] Cell-Free DNA/Toll-like Receptor 9 Axis Plays a Pivotal Role in Metabolic Disorder-induced Chronic Inflammation, Leading to Atherogenesis and Insulin Resistance. (2016)
  • Author(s): Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Soeki T, Shimabukuro M, Sata M
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター(宮城県仙台市）
  • Year and Date: 2016-03-18
• [Presentation] TLR9の活性化は虚血肢における炎症を増強し血流改善を遅延させる (2016)
  • Author(s): 六車隆太郎、福田大受、西本幸子、東邦康智、田中君枝、平田陽一郎、八木秀介、添木武、島袋充生、佐田政隆
  • Organizer: 第45回日本心脈管作動物質学会
  • Place of Presentation: 阿波観光ホテル(徳島県徳島市）
  • Year and Date: 2016-02-05
• [Presentation] 動脈硬化におけるマクロファージTLR9の役割 (2016)
  • Author(s): 西本幸子、福田大受、東邦康智、田中君枝、平田陽一郎、八木秀介、添木武、阪上浩、島袋充生、佐田政隆
  • Organizer: 第45回日本心脈管作動物質学会
  • Place of Presentation: 阿波観光ホテル(徳島県徳島市）
  • Year and Date: 2016-02-05
• [Presentation] Dipeptidyl peptidase-4 inhibitor, linagliptin, ameliorates endothelial dysfunction and atherogenesis in apolipoprotein-E deficient mice through GLP-1 dependent and independent manners (2016)
  • Author(s): Hotimah Masdan Salim、福田大受、東邦康智、田中君枝、平田陽一郎、八木秀介、添木武、島袋充生、佐田政隆
  • Organizer: 第45回日本心脈管作動物質学会
  • Place of Presentation: 阿波観光ホテル(徳島県徳島市）
  • Year and Date: 2016-02-05
• [Presentation] ω3系不飽和脂肪酸の脂質ラフト構造変化を介した抗動脈硬化作用の解明 (2016)
  • Author(s): 高島啓、福田大受、田中君枝、東邦康智、平田陽一郎、山田博胤、添木武、若槻哲三、島袋充生、佐田政隆
  • Organizer: 第45回日本心脈管作動物質学会
  • Place of Presentation: 阿波観光ホテル(徳島県徳島市）
  • Year and Date: 2016-02-05
• [Presentation] 動脈硬化発症におけるマクロファージToll-like receptor 9の役割 (2015)
  • Author(s): 西本幸子、福田大受、阪上浩、島袋充生、佐田政隆
  • Organizer: CVMW2015
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市）
  • Year and Date: 2015-12-10
• [Presentation] Dipeptidyl Peptidase-4 Inhibitor, Linagliptin, Ameliorates Endothelial Dysfunction and the Development of Atherosclerosis in Normoglycemic Apolipoprotein-E Deficient Mice (2015)
  • Author(s): Salim HM, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Soeki T, Shimabukuro M, Sata M
  • Organizer: CVMW2015
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市）
  • Year and Date: 2015-12-10
• [Presentation] 自己遊離核酸断片の認識を介した血管の炎症と動脈硬化発症メカニズム (2015)
  • Author(s): 福田大受、西本幸子、東邦康智、田中君枝、平田陽一郎、八木秀介、添木武、島袋充生、佐田政隆
  • Organizer: CVMW2015
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市）
  • Year and Date: 2015-12-10
• [Presentation] FXa - PAR-2経路は血管の慢性炎症を惹起し動脈硬化を促進する (2015)
  • Author(s): 原知也、福田大受、田中君枝、東邦康智、平田陽一郎、八木秀介、添木 武、島袋充生、佐田政隆
  • Organizer: CVMW2015
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市）
  • Year and Date: 2015-12-10
• [Presentation] Toll-like Receptor 9 Plays a Pivotal Role in Angiotensin II-induced Atherosclerosis (2015)
  • Author(s): Nishimoto S, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Soeki T, Sakaue H, Shimabukuro M, Sata M.
  • Organizer: AHA Scientific Sessions 2015
  • Place of Presentation: Orlando (USA)
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Hematopoietic Protease-activated Receptor-2 Plays a Critical Role in Vascular Inflammation and Atherosclerosis in ApoE-Deficient Mice (2015)
  • Author(s): Hara T, Fukuda D, Tanaka K, Higashikuni Y, Hirata Y, Yagi S, Yamada H, Soeki T, Wakatsuki T, Shimabukuro M, Sata M.
  • Organizer: AHA Scientific Sessions 2015
  • Place of Presentation: Orlando (USA)
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] N-3 Polyunsaturated Fatty Acids Inhibit Inflammatory Responses in Macrophages by the Reduction of Toll-like Receptor 4 Expression in Lipid Rafts, Leading to the Suppression of Atherogenesis in Apolipoprotein E Deficient Mice (2015)
  • Author(s): Takashima A, Fukuda D, Tanaka K, Higashikuni Y, Hirata Y, Yamada H, Soeki T, Wakatsuki T, Shimabukuro M, Sata M
  • Organizer: AHA Scientific Sessions 2015
  • Place of Presentation: Orlando (USA)
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Dipeptidyl Peptidase-4 Inhibitor, Linagliptin, Ameliorates Endothelial Dysfunction and Atherogenesis in Apolipoprotein-e Deficient Mice Through GLP-1 Dependent and Independent Manners (2015)
  • Author(s): Salim HM, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Soeki T, Shimabukuro M, Sata M.
  • Organizer: AHA Scientific Sessions 2015
  • Place of Presentation: Orlando (USA)
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] The activation of toll-like receptor 9 deteriorates blood flow recovery after hind-limb ischemia. (2015)
  • Author(s): Nishimoto S, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Soeki T, Sakaue H, Shimabukuro M, Sata M
  • Organizer: ESC Congress 2015
  • Place of Presentation: London (UK)
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] 活性型第X凝固因子によるマクロファージ活性化を介した新しい動脈硬化進展機序の検討 (2015)
  • Author(s): 原知也、福田大受、田中君枝、東邦康智、平田陽一郎、八木秀介、山田博胤、添木武、若槻哲三、島袋充生、佐田政隆
  • Organizer: 第2回日本心血管脳卒中学会学術集会
  • Place of Presentation: ホテルクレメント徳島(徳島県徳島市）
  • Year and Date: 2015-06-12
• [Presentation] Inhibition of Activated Factor X Attenuates Vascular Inflammation and Atherosclerosis in ApoE-deficient Mice (2015)
  • Author(s): Hara T, Fukuda D, Tanaka K, Higashikuni Y, Hirata Y, Yagi S, Yamada H, Soeki T, Wakatsuki T, Shimabukuro M, Sata M
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪府大阪市）
  • Year and Date: 2015-04-24
• [Presentation] Inhibition of Activated Factor X Attenuates Neointima Formation after Wire-Mediated Vascular Injury. (2015)
  • Author(s): Hara T, Fukuda D, Tanaka K, Higashikuni Y, Hirata Y, Yagi S, Yamada H, Soeki T, Wakatsuki T, Shimabukuro M, Sata M
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪府大阪市）
  • Year and Date: 2015-04-24
• [Presentation] Genetic Deletion of Toll-like Receptor 9 Accelerates Blood Flow Recovery after Hindlimb Ischemia. (2014)
  • Author(s): Nishimoto S, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Soeki T, Sakaue H, Shimabukuro M, Sata M.
  • Organizer: AHA Scientific Sessions 2014
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Genetic ablation of TLR9 improves insulin resistance through macrophage accumulation in adipose tissue (2013)
  • Author(s): Sachiko Nishimoto, Daiju Fukuda, Michio Shimabukuro, Masayoshi Ishida, Sachiko Matsumoto, Shusuke Yagi, Takeshi Soeki, Hiroshi Sakaue, Yutaka Nakaya, Masataka Sata
  • Organizer: European Society of Cardiology
  • Place of Presentation: アムステルダム（オランダ）、RAI CONVENTION CENTER
• [Presentation] Macrophage Toll-like receptor 9 Signaling Contributes to the Development of Insulin Resistance through the Promotion of Inflammation in Adipose Tissue (2013)
  • Author(s): Sachiko Nishimoto, Daiju Fukuda, Michio Shimabukuro, Masayoshi Ishida, Sachiko Matsumoto, Shusuke Yagi, Takeshi Soeki, Hiroshi Sakaue, Yutaka Nakaya, Masataka Sata
  • Organizer: American Heart association Scientific Sessions 2013
  • Place of Presentation: ダラス（米国）、Dallas Convention Center