Functional role of pathogen sensors and their endogenous ligands in the metabolic syndrome

2013 Fiscal Year Final Research Report

• Project Area: Homeostatic inflammation: Molecular basis and dysregulation
• Project/Area Number: 21117007
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: OGAWA Yoshihiro 東京医科歯科大学, 医歯(薬)学総合研究科, 教授 (70291424)
• Co-Investigator(Kenkyū-buntansha): SATA Masataka 徳島大学, 大学院ヘルスバイオサイエンス研究部, 教授 (80345214)
• Project Period (FY): 2009-07-23 – 2014-03-31
• Keywords: メタボリックシンドローム / 病原体センサー / 内因性リガンド / マクロファージ / 脂肪酸

Research Abstract

In this study, we investigated novel molecular mechanisms underlying the metabolic syndrome, especially focusing on "homeostatic inflammation" that consists of pathogen sensors and their endogenous ligands. We have already demonstrated that the saturated fatty acid-TLR4 pathway plays an important role in the pathophysiology of obesity-induced adipose tissue inflammation. In addition, our data show that ATF4 and ATF3, metabolic stress-induced transcription factors, positively and negatively regulate the TLR4 pathway, respectively. Moreover, Mincle, a pathogen sensor that selectively expressed in macrophages from obese adipose tissue, is a novel regulator of adipose tissue inflammation.

Research Products

• [Journal Article] Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages (2014)
  • Author(s): Y. Iwasaki, T. Suganami, R. Hachiya, I. Shirakawa, M. Kim-Saijo, M. Tanaka, M. Hamaguchi, T. Takai-Igarashi, M. Nakai, Y. Miyamoto, Y. Ogawa
  • Journal Title: Diabetes Volume: 63 Pages: 152-161
  • DOI: 10.2337/db13-0757
  • Peer Reviewed
• [Journal Article] Human TLR4 polymorphism D299G/T399I alters TLR4/MD-2 conformation and response to a weak ligand monophosphoryl lipid A (2013)
  • Author(s): N. Yamakawa, U. Ohto, S. Akashi-Takamura, K. Takahashi, SI. Saitoh, N. Tanimura, T. Suganami, Y. Ogawa, T. Shibata, T. Shimizu, K. Miyake
  • Journal Title: Int. Immunol. Volume: 25 Pages: 45-52
  • DOI: 10.1093/intimm/dxs084
  • Peer Reviewed
• [Journal Article] Association between body weight at weaning and remodeling in the subcutaneous adipose tissue of obese adult mice with undernourishment in utero (2013)
  • Author(s): Y.K. Kohmura, N. Kanayama, K. Muramatsu, N. Tamura, C. Yaguchi, T. Uchida, K. Suzuki, K. Sugihara, S. Aoe, T. Sasaki, T. Suganami, Y. Ogawa, H. Itoh
  • Journal Title: Reprod. Sci. Volume: 20 Pages: 813-827
  • DOI: 10.1177/1933719112466300
  • Peer Reviewed
• [Journal Article] Hepatic crown-like structure : a unique histological feature in non-alcoholic steatohepatitis in mice and humans (2013)
  • Author(s): M. Itoh, H. Kato, T. Suganami, K. Konuma, Y. Marumoto, S. Terai, H. Sakugawa, S. Kanai, M. Hamaguchi, T. Fukaishi, S. Aoe, K. Akiyoshi, Y. Komohara, M. Takeya, I. Sakaida, Y. Ogawa
  • Journal Title: PLoS ONE Volume: 8 Pages: e82163
  • DOI: 10.1371/journal.pone.0082163
  • Peer Reviewed
• [Journal Article] Exendin-4, a glucagon-like peptide-1 receptor agonist, attenuates neointimal hyperplasia after vascular injury (2013)
  • Author(s): Y. Hirata, H. Kurobe, C. Nishio, K. Tanaka, D. Fukuda, E. Uematsu, S. Nishimoto, T. Soeki, N. Harada, H. Sakaue, T. Kitagawa, M. Shimabukuro, N. Nakaya, M. Sata
  • Journal Title: Eur. J. Pharmacol. Volume: 699 Pages: 106-111
  • DOI: 10.1016/j.ejphar.2012.11.057
  • Peer Reviewed
• [Journal Article] Beneficial effect of a synthetic prostacyclin agonist, ONO-1301, in rat autoimmune myocarditis model (2013)
  • Author(s): Y. Hirata, H. Kurobe, E. Uematsu, S. Yagi, T. Soeki, H. Yamada, D. Fukuda, M. Shimabukuro, M. Nakayama, K. Matsumoto, Y. Sakai, T. Kitagawa, M. Sata
  • Journal Title: Eur. J. Pharmacol. Volume: 699 Pages: 81-87
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  • Peer Reviewed
• [Journal Article] HMGB1 plays a critical role in vascular inflammation and lesion formation via toll-like receptor 9 (2013)
  • Author(s): Y. Hirata, H. Kurobe, M. Higashida, D. Fukuda, M. Shimabukuro, Y. Higashikuni, T. Kitagawa, M. Sata
  • Journal Title: Atherosclerosis Volume: 231 Pages: 227-233
  • DOI: 10.1016/j.atherosclerosis.2013.09.010
  • Peer Reviewed
• [Journal Article] Epicardial adipose tissue volume and adipocytokine imbalance are strongly linked to human coronary atherosclerosis (2013)
  • Author(s): M. Shimabukuro, Y. Hirata, M. Tabata, M. Dagvasumberel, H. Sato, H. Kurobe, D. Fukuda, T. Soeki, T. Kitagawa, S. Takanashi, M. Sata
  • Journal Title: Arterioscler. Thromb. Vasc. Biol. Volume: 33 Pages: 1077-1084
  • DOI: 10.1161/ATVBAHA.112.300829
  • Peer Reviewed
• [Journal Article] The Radioprotective 105/MD-1 complex contributes to diet-induced obesity and adipose tissue inflammation (2012)
  • Author(s): Y. Watanabe, T. Nakamura, S. Ishikawa, S. Fujisaka, I. Usui, K. Tsuneyama, Y. Ichihara, T. Wada, Y. Hirata, T. Suganami, H. Izaki, S. Akira, K. Miyake, H. Kanayama, M. Shimabukuro, M. Sata, T. Sasaoka, Y. Ogawa, K. Tobe, K. Takatsu, Y. Nagai
  • Journal Title: Diabetes Volume: 61 Pages: 1199-1209
  • DOI: 10.2337/db11-1182
  • Peer Reviewed
• [Journal Article] Role of DNA methylation in the regulation of lipogenic glycerol-3-phosphate acyltransferase 1 gene expression in the mouse neonatal liver (2012)
  • Author(s): T. Ehara, Y. Kamei, M. Takahashi, X. Yuan, S. Kanai, E. Tamura, M. Tanaka, T. Yamazaki, S. Miura, O. Ezaki, T. Suganami, M. Okano, Y. Ogawa
  • Journal Title: Diabetes Volume: 61 Pages: 2442-2450
  • Peer Reviewed
• [Journal Article] Highly purified eicosapentaenoic acid increases interleukin-10 levels of peripheral blood monocytes in obese patients with dyslipidemia (2012)
  • Author(s): N. Satoh-Asahara, A. Shimatsu, Y. Sasaki, H. Nakaoka, A. Himeno, M. Tochiya, S. Kono, T. Takaya, K. Ono, H. Wada, T. Suganami, K. Hasegawa, Y. Ogawa
  • Journal Title: Diabetes Care Volume: 35 Pages: 2631-2639
  • DOI: 10.2337/dc12-0269
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• [Journal Article] Adipose tissue inflammation and ectopic lipid accumulation. (review) (2012)
  • Author(s): T. Suganami, M. Tanaka, Y. Ogawa
  • Journal Title: Endocr. J. Volume: 59 Pages: 849-857
  • Peer Reviewed
• [Journal Article] The ATP-binding cassette transporter ABCG2 protects against pressure overload-induced cardiac hypertrophy and heart failure by promoting angiogenesis and antioxidant response (2012)
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  • Journal Title: Arterioscler. Thromb. Vasc. Biol. Volume: 32 Pages: 654-661
  • DOI: 10.1161/ATVBAHA.110.211755
  • Peer Reviewed
• [Journal Article] Increased expression of macrophage-inducible C-type lectin in adipose tissue of obese mice and humans (2011)
  • Author(s): M. Ichioka, T. Suganami, N. Tsuda, I. Shirakawa, Y. Hirata, N. Satoh-Asahara, Y. Shimoda, M. Tanaka, M. Kim-Saijo, Y. Miyamoto, Y. Kamei, M. Sata, Y. Ogawa
  • Journal Title: Diabetes Volume: 60 Pages: 819-826
  • DOI: 10.2337/db10-0864
  • Peer Reviewed
• [Journal Article] The Japan Obesity Metabolic Syndrome Study (JOMS) Group. Urinary cystatin C as a potential risk marker for cardiovascular disease and chronic kidney disease in patients with obesity and metabolic syndrome (2011)
  • Author(s): N. Satoh-Asahara, T. Sugamami, T. Majima, K. Kotani, Y. Kato, R. Araki, K. Koyama, T. Okajima, M. Tanabe, M. Oishi, A. Himeno, S. Kono, A. Sugawara, M. Hattori, Y. Ogawa, A. Shimatsu
  • Journal Title: Clin. J. Am. Soc. Nephrol. Volume: 6 Pages: 265-273
  • DOI: 10.2215/CJN.04830610
  • Peer Reviewed
• [Journal Article] Role of central leptin signaling in the starvation-induced alteration of B cell development (2011)
  • Author(s): M. Tanaka, T. Suganami, M. Kim-Saijo, C. Toda, M. Tsuiji, K. Ochi, Y. Kamei, Y. Minokoshi, Y. Ogawa
  • Journal Title: J. Neurosci. Volume: 31 Pages: 8373-8380
  • DOI: 10.1523/JNEUROSCI.6562-10.2011
  • Peer Reviewed
• [Journal Article] Melanocortin-4 receptor-deficient mice as a novel mouse model of non-alcoholic steatohepatitis (2011)
  • Author(s): M. Itoh, T. Suganami, N. Nakagawa, M. Tanaka, Y. Yamamoto, Y. Kamei, S. Terai, I. Sakaida, Y. Ogawa
  • Journal Title: Am. J. Pathol. Volume: 179 Pages: 2454-2463
  • DOI: 10.1016/j.ajpath.2011.07.014
  • Peer Reviewed
• [Journal Article] Adipose tissue remodeling as homeostatic inflammation. (review) (2011)
  • Author(s): M. Itoh, T. Suganami, R. Hachiya, Y. Ogawa
  • Journal Title: Int. J. Inflam. Volume: 2011 Pages: 720926
  • DOI: 10.4061/2011/720926
  • Peer Reviewed
• [Journal Article] Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue (2011)
  • Author(s): Y. Hirata, M. Tabata, H. Kurobe, T. Motoki, M. Akaike, C. Nishio, M. Higashida, H. Mikasa, Y. Nakaya, S. Takanashi, T. Igarashi, T. Kitagawa, M. Sata
  • Journal Title: J. Am. Coll. Cardiol. Volume: 58 Pages: 248-255
  • DOI: 10.1016/j.jacc.2011.01.048
  • Peer Reviewed
• [Journal Article] Augmented angiogenesis in adventitia promotes growth of atherosclerotic plaque in apolipoprotein E-deficient mice (2011)
  • Author(s): K. Tanaka, D. Nagata, Y. Hirata, Y. Tabata, R. Nagai, M. Sata
  • Journal Title: Atherosclerosis Volume: 215 Pages: 366-373
  • DOI: 10.1016/j.atherosclerosis.2011.01.016
  • Peer Reviewed
• [Journal Article] Role of central leptin signaling in renal macrophage infiltration (2010)
  • Author(s): M. Tanaka, T. Suganami, S. Sugita, Y. Shimoda, M. Kasahara, S. Aoe, M. Takeya, S. Takeda, Y. Kamei, Y. Ogawa
  • Journal Title: Endocr. J. Volume: 57 Pages: 61-72
  • Peer Reviewed
• [Journal Article] Unbalanced M1/M2 phenotype of peripheral blood monocytes in obese diabetic patients : effect of pioglitazone (2010)
  • Author(s): N. Satoh, A. Shimatsu, A. Himeno, Y. Sasaki, H. Yamakage, K. Yamada, T. Suganami, Y. Ogawa
  • Journal Title: Diabetes Care Volume: 33 Pages: e7
  • DOI: 10.2337/dc09-1315
  • Peer Reviewed
• [Journal Article] Insulin-induced ectodomain shedding of heparin-binding epidermal growth factor-like growth factor in adipocytes in vitro (2010)
  • Author(s): T. Yamamoto, T. Suganami, M. Kiso-Narita, PA. Scherle, Y. Kamei1, M. Isobe, S. Higashiyama, Y. Ogawa
  • Journal Title: Obesity Volume: 18 Pages: 1888-1894
  • DOI: 10.1038/oby.2010.2
  • Peer Reviewed
• [Journal Article] Adipose tissue macrophages : their role in adipose tissue remodeling. (review) (2010)
  • Author(s): T. Suganami, Y. Ogawa
  • Journal Title: J. Leukoc. Biol. Volume: 88 Pages: 33-39
  • DOI: 10.1189/jlb.0210072
  • Peer Reviewed
• [Journal Article] Role of transient receptor potential vanilloid 2 in LPS-induced cytokine production in macrophages (2010)
  • Author(s): K. Yamashiro, T. Sasano, K. Tojo, I. Namekata, J. Kurokawa, N. Sawada, T. Suganami, Y. Kamei, H. Tanaka, N. Tajima, K. Utsunomiya, Y. Ogawa, T. Furukawa
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 398 Pages: 284-289
  • Peer Reviewed
• [Journal Article] Anti-obesity effect of eicosapentaenoic acid in high-fat/high-sucrose diet-induced obesity : importance of hepatic lipogenesis (2010)
  • Author(s): A. Sato, H. Kawano, T. Notsu, M. Ohta, M. Nakakuki, K. Mizuguchi, M. Itoh, T. Suganami, Y. Ogawa
  • Journal Title: Diabetes Volume: 59 Pages: 2495-2504
  • DOI: 10.2337/db09-1554
  • Peer Reviewed
• [Journal Article] Endovascular injury induces rapid phenotypic changes in perivascular adipose tissue (2010)
  • Author(s): M. Takaoka, H. Suzuki, S. Shioda, K. Sekikawa, Y. Saito, R. Nagai, M. Sata
  • Journal Title: Arterioscler. Thromb. Vasc. Biol. Volume: 30 Pages: 1576-1582
  • DOI: 10.1161/ATVBAHA.110.207175
  • Peer Reviewed
• [Journal Article] Bone marrow-derived cells contribute to vascular inflammation but do not differentiate into smooth muscle cell lineages (2010)
  • Author(s): H. Iwata, I. Manabe, K. Fujiu, T. Yamamoto, N. Takeda, K. Eguchi, A. Furuya, M. Kuro-o, M. Sata, R. Nagai
  • Journal Title: Circulation Volume: 122 Pages: 2048-2057
  • DOI: 10.1161/CIRCULATIONAHA.110.965202
  • Peer Reviewed
• [Journal Article] Activating transcription factor 3 constitutes a negative feedback mechanism that attenuates saturated fatty acid/Toll-like receptor 4 signaling and macrophage activation in obese adipose tissue (2009)
  • Author(s): T. Suganami, X. Yuan, Y. Shimoda, K. Uchio-Yamada, N. Nakagawa, I. Shirakawa, T. Usami, T. Tsukahara, K. Nakayama, Y. Miyamoto, K. Yasuda, J. Matsuda, Y. Kamei, S. Kitajima, Y. Ogawa
  • Journal Title: Circ. Res. Volume: 105 Pages: 25-32
  • DOI: 10.1161/CIRCRESAHA.109.196261
  • Peer Reviewed
• [Journal Article] Highly purified eicosapentaenoic acid reduces cardio-ankle vascular index in association with decrease in serum amyloid A-LDL in metabolic syndrome (2009)
  • Author(s): N. Satoh, A. Shimatsu, K. Kotani, A. Himeno, T. Majima, K. Yamada, T. Suganami, Y. Ogawa
  • Journal Title: Hypertens. Res. Volume: 32 Pages: 1004-1008
  • DOI: 10.1038/hr.2009.145
  • Peer Reviewed
• [Journal Article] Periadventitial adipose tissue plays a critical role in vascular remodeling (2009)
  • Author(s): M. Takaoka, D. Nagata, S. Kihara, S. Shimomura, Y. Kimura, Y. Tabata, Y. Saito, R. Nagai, M. Sata
  • Journal Title: Circ. Res. Volume: 105 Pages: 906-911
  • DOI: 10.1161/CIRCRESAHA.109.199653
  • Peer Reviewed
• [Presentation] Epicardial adipose tissue plays a role in the pathogenesis of atherosclerosis (2014)
  • Author(s): M. Sata
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20140414-17
• [Presentation] Role of parenchymal-stromal cell interaction in metabolic diseases (2014)
  • Author(s): Y. Ogawa
  • Organizer: 2014 Keystone Symposia on Molecular and Cellular Biology: Innate Immunity, Metabolism and Vascular Injury
  • Place of Presentation: Whistler, Canada
  • Year and Date: 20140323-28
• [Presentation] Regulation of metabolic genes by DNA methylation (2013)
  • Author(s): Y. Ogawa
  • Organizer: 8th World Congress on Developmental Origins of Health and Disease
  • Place of Presentation: SUTEC, Singapore
  • Year and Date: 20131117-20
• [Presentation] Chronic inflammation and ectopic fat accumulation in the metabolic syndrome (2013)
  • Author(s): Y. Ogawa
  • Organizer: 2013 International Conference on Diabetes and Metabolism (ICDM2013) & 5th Scientific Meeting of the Asian Association for the Study of Diabetes (5th AASD Scientific Meeting)
  • Place of Presentation: Seoul, Korea
  • Year and Date: 20131106-09
• [Presentation] Inflammation in atherosclerosis and adipose tissue (2012)
  • Author(s): M. Sata
  • Organizer: The 12th Biennial International Endotoxin & Innate Immunity Society (IEIIS) Meeting 2012
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 20121023-26
• [Presentation] Epicardial adipose tissue plays a role in the pathogenesis of Atherosclerosis (2012)
  • Author(s): M. Sata
  • Organizer: APSC Subspecialty Congress-Intervention and Imaging 2012
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 20120504-06
• [Presentation] Chronic inflammation and ectopic fat accumulation in the metabolic syndrome (2012)
  • Author(s): Y. Ogawa
  • Organizer: The 2012 Spring Conference of the Korean Association of Immunologists
  • Place of Presentation: Seoul, Korea
  • Year and Date: 20120412-13
• [Presentation] Chronic inflammation, a molecular basis underlying the metabolic syndrome (2012)
  • Author(s): Y. Ogawa
  • Organizer: 2012 Shanghai Symposium on Obesity & Diabetes
  • Place of Presentation: Shanghai, China
  • Year and Date: 2012-04-07
• [Presentation] Homeostatic inflammation : a molecular basis underlying metabolic diseases (2011)
  • Author(s): Y. Ogawa
  • Organizer: International Symposium on Inflammation and Disease
  • Place of Presentation: Academia Sinica, Taiwan
  • Year and Date: 20110908-09
• [Presentation] Epigenetic regulation of metabolic diseases (2011)
  • Author(s): Y. Ogawa
  • Organizer: The Endocrine Society's 93rd Annual Meeting & Expo (ENDO 2011)
  • Place of Presentation: Boston, USA
  • Year and Date: 20110604-07
• [Presentation] Adipose tissue remodeling as homeostatic inflammation (2010)
  • Author(s): Y. Ogawa
  • Organizer: The 8th International Diabetes Federation-Western Pacific Region (IDF-WPR) Congress
  • Place of Presentation: Busan, Korea
  • Year and Date: 20101017-20
• [Presentation] Vascular injury and repair : beyond the endothelium (2010)
  • Author(s): M. Sata
  • Organizer: ESC CONGRESS 2010
  • Place of Presentation: Stockholm,Sweden
  • Year and Date: 20100828-0901
• [Remarks]
  • URL: http://www.tmd.ac.jp/grad/cme/index.html
• [Remarks]
  • URL: http://square.umin.ac.jp/TOKUSHIM/
• [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 (2011)
  • 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 Rights Type: 特許
  • Industrial Property Number: 第4862160号
  • Acquisition Date: 2011-11-18