Elucidation of the mechanism of the innate immune signal that induces hypothalamic inflammation and feeding dysfunction

• Project/Area Number: 15K08527
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: University of Toyama
• Principal Investigator: NAGAI Yoshinori 富山大学, 大学院医学薬学研究部(医学), 客員教授 (30431761)
• Co-Investigator(Renkei-kenkyūsha): WATANABE Yasuharu 富山大学, 大学院医学薬学研究部(医学), 客員准教授 (80646307)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 自然免疫 / 視床下部炎症 / 摂食異常 / レプチン抵抗性

Outline of Final Research Achievements

We found that a TLR signaling molecule TRIF had an important role in the pathogenesis of high-fat diet (HFD)-induced hypothalamic inflammation and leptin resistance. We demonstrated that TRIF was expressed in the hypothalamus of wild-type mice by in situ hybridization. In vivo analyses revealed that HFD- or an intrinsic TLR3 ligand Stathmin-induced inflammation and reduced leptin signaling in the hypothalamus were improved in TRIF-deficent mice compared with wild-type mice. However, TLR3-deficent mice showed different phenotypes from TRIF-deficent mice, suggesting that another molecule other than TLR3 may be responsible for TRIF-induced hypothalamic inflammation and leptin resistance.

Research Products

• [Journal Article] A subset of cerebrovascular pericytes originates from mature macrophages in the very early phase of vascular development in CNS. (2017)
  • Author(s): S. Yamamoto, M. Muramatsu, E. Azuma, M. Ikutani, Y. Nagai, H. Sagara, B.N. Koo, S. Kita, E. O’Donnell, T. Osawa, H. Takahashi, K.I. Takano, M. Dohmoto, M. Sugimori, I. Usui, Y. Watanabe, N. Hatakeyama, T. Iwamoto, I. Komuro, K. Takatsu, K. Tobe, S. Niida, N. Matsuda, M. Shibuya, M. Sasahara
  • Journal Title: Sci Rep Volume: 7：3855 Issue: 1 Pages: 1-16
  • DOI: 10.1038/s41598-017-03994-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD206+ M2-like macrophages regulate systemic glucose metabolism by inhibiting proliferation of adipocyte progenitors (2017)
  • Author(s): Nawaz Allah, , Usui Isao, , et al
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 286-301
  • DOI: 10.1038/s41467-017-00231-1
  • NAID: 120006535075
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Funiculosin variants and phosphorylated derivatives promote innate immune responses via the Toll-like receptor 4/myeloid differentiation factor-2 complex (2017)
  • Author(s): Okamoto N, Mizote K, Honda H, Saeki A, Watanabe Y, Yamaguchi-Miyamoto T, Fukui R, Tanimura N, Motoi Y, Akashi-Takamura S, Kato T, Fujishita S, Kimura T, Ohto U, Shimizu T, Hirokawa T, Miyake K, Fukase K, Fujimoto Y, Nagai Y, Takatsu K
  • Journal Title: Journal of Biological Chemistry Volume: 292 Issue: 37 Pages: 15378-15394
  • DOI: 10.1074/jbc.m117.791780
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Eplerenone prevented obesity-induced inflammasome activation and glucose intolerance (2017)
  • Author(s): Wada T, Ishikawa A, Watanabe E, Nakamura Y, Aruga Y, Hasegawa H, Onogi Y, Honda H, Nagai Y, Takatsu K, Ishii Y, Sasahara M, Koya D, Tsuneki H, Sasaoka T
  • Journal Title: J Endocrinol. Volume: 235 Issue: 3 Pages: 179-191
  • DOI: 10.1530/joe-17-0351
  • Peer Reviewed
• [Journal Article] Allergic diseases: From bench to clinic - Contribution of the discovery of interleukin-5 (2017)
  • Author(s): Yanagibashi T、Satoh M、Nagai Y、Koike M、Takatsu K
  • Journal Title: Cytokine Volume: 98 Pages: 59-70
  • DOI: 10.1016/j.cyto.2016.11.011
  • Peer Reviewed
• [Journal Article] Inflammatory responses increase secretion of MD-1 protein (2016)
  • Author(s): Thomas Jennings R, Odkhuu E, Nakashima A, Morita N, Kobayashi T, Yamai I, Tanaka M, Suganami T, Haga S, Ozaki M, Watanabe Y, Nagai Y, Takatsu K, Kikuchi-Ueda T, Ichimonji I, Ogawa Y, Takagi H, Yamazaki T, Miyake K, Akashi-Takamura S
  • Journal Title: International Immunology Volume: 28 Issue: 10 Pages: 503-512
  • DOI: 10.1093/intimm/dxw031
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HIF-1α in Myeloid Cells Promotes Adipose Tissue Remodeling Toward Insulin Resistance. (2016)
  • Author(s): Takikawa A, Mahmood A, Nawaz A, Kado T, Okabe K, Yamamoto S, Arif A, Senda S, Tsuneyama K, Ikutani M, Watanabe Y, Igarashi Y, Nagai Y, Takatsu K, Koizumi K, Imura J, Goda N, Sasahara M, Matsumoto M, Saeki K, Nakagawa T, Fujisaka S, Usui I, Tobe K.
  • Journal Title: Diabetes Volume: 65(12) Issue: 12 Pages: 3649-3659
  • DOI: 10.2337/db16-0012
  • NAID: 40021380120
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fetal lymphoid progenitors become restricted to B-1 fates coincident with IL-7Rα expression (2016)
  • Author(s): Iida R, Shinoda K, Hattori Y, Nagai Y, Takatsu K, Kouro T
  • Journal Title: PLoS ONE Volume: 11 Issue: 10 Pages: e0165676-e0165676
  • DOI: 10.1371/journal.pone.0165676
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Potential therapeutic natural products for the treatment of obesity-associated inflammation by targeting TLRs and inflammasomes (2016)
  • Author(s): Nagai Y, Honda H, Watanabe Y, Takatsu K
  • Journal Title: Chronic Inflammation -Mechanisms and Regulation- Volume: なし Pages: 379-397
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Deletion of SIRT1 in myeloid cells impairs glucose metabolism with enhancing inflammatory response to adipose tissue hypoxia (2016)
  • Author(s): Akiko Takikawa, Isao Usui , Shiho Fujisaka, Masashi Ikutani, Satoko Senda, Shinpei Hattori, Koichi Tsuneyama, Yukiko Koshimizu, Ran Inoue, Ayumi Tanaka-Hayashi, Takashi Nakagawa, Yoshinori Nagai, Kiyoshi Takatsu, Toshiyasu Sasaoka, Hisashi Mori, Kazuyuki Tobe
  • Journal Title: Diabetology International Volume: 7 Issue: 1 Pages: 59-68
  • DOI: 10.1007/s13340-015-0213-3
  • NAID: 40020774323
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glycyrrhetinic acid inhibits contact hypersensitivity induced by trichophytin via dectin-1 (2016)
  • Author(s): Tomoya Nakamura, Akiko Nishibu, Naoki Yoshida, Mitsue Yasoshima, Kazushi Anzawa, Yasuharu Watanabe, Yoshinori Nagai, Kiyoshi Takatsu, Kazuo Ogawa, Takashi Mochizuki
  • Journal Title: Experimental Dermatology Volume: 25 Issue: 4 Pages: 299-304
  • DOI: 10.1111/exd.12931
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Isoliquiritigenin attenuates adipose tissue inflammation in vitro and adipose tissue fibrosis through inhibition of innate immune responses in mice. (2016)
  • Author(s): Watanabe Y, Nagai Y, Honda H, Okamoto N, Yamamoto S, Hamashima T, Ishii Y, Tanaka M, Suganami T, Sasahara M, Miyake, K, Takatsu K.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 23097-23097
  • DOI: 10.1038/srep23097
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 自然免疫系センサーによる慢性炎症制御とメタボリック症候群 (2015)
  • Author(s): 長井良憲, 渡邉康春, 高津聖志
  • Journal Title: 別冊BIO Clinica 慢性炎症と疾患「慢性炎症制御による加齢関係疾患治療の展望」 Volume: 4 Pages: 67-72
• [Presentation] 糖尿病モデルマウスの内臓脂肪組織に対するイソリクイリチゲニンの抗炎症・抗線維化作用の解析 (2018)
  • Author(s): 本田裕恵, 渡邉康春, 長井良憲, 松永孝之, 岡本直樹, 平井嘉勝, 高津聖志
  • Organizer: 日本薬学会 第138年会
• [Presentation] Funiculosin variants and their synthetic derivatives are novel agonists for murine and human TLR4/MD-2 complex: Potential reagents for developing vaccine adjuvants (2017)
  • Author(s): Yoshinori Nagai, Naoki Okamoto, Kiyoshi Takatsu
  • Organizer: Innovation Forums Basel Life 2017
  • Int'l Joint Research
• [Presentation] The interaction of neutrophils with adipocytes plays a key role in the infiltration of macrophage into the adipose tissue (2017)
  • Author(s): Yasuharu Watanabe, Yoshinori Nagai, Kiyoshi Takatsu
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] IL-5-producing ILC2s in the large intestine contribute to T cell-independent IgA production through the regulation of eosinophil homeostasis (2017)
  • Author(s): Tsutomu Yanagibashi, Masashi Ikutani, Yoshinori Nagai, Kiyoshi Takatsu
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Agonistic effects of synthetic derivatives of funiculosin on mouse/human TLR4/MD-2 (2016)
  • Author(s): Naoki Okamoto, Hiroe Honda, Sachiko Akashi-Takamura, Yoshinori Nagai, Kiyoshi Takatsu
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター
  • Year and Date: 2016-12-05
• [Presentation] Adipose tissue neutrophils are primed by the interaction with adipocytes (2016)
  • Author(s): Yasuharu Watanabe, Yoshinori Nagai, Kiyoshi Takatsu
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター
  • Year and Date: 2016-12-05
• [Presentation] 天然薬物イソリクイリチゲニンは自然免疫系に作用し、内臓脂肪組織の線維化を抑制する (2016)
  • Author(s): 渡邉康春, 長井良憲, 本田裕恵, 高津聖志
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京ファッションタウン
  • Year and Date: 2016-10-07
• [Presentation] 甘草成分イソリクイリチゲニンは内臓脂肪組織の炎症・線維化を抑制する (2016)
  • Author(s): 本田裕恵, 渡邉康春, 長井良憲, 松永孝之, 岡本直樹, 平井嘉勝, 高津聖志
  • Organizer: 日本生薬学会第63回年会
  • Place of Presentation: 富山国際会議場
  • Year and Date: 2016-09-24
• [Presentation] TLRのアダプター分子TRIFを介した視床下部炎症と摂食制御異常の解析 (2016)
  • Author(s): 渡邉康春, 長井良憲, 高津聖志
  • Organizer: 第37回日本炎症・再生医学会
  • Place of Presentation: 京都市勧業館みやこめっせ
  • Year and Date: 2016-06-16
• [Presentation] 甘草成分イソリクイリチゲニンはNLRP3インフラマソーム活性化を阻害し、2型糖尿病の慢性炎症を改善する (2016)
  • Author(s): 本田裕恵, 長井良憲, 松永孝之, 岡本直樹, 渡邉康春, 常山幸一, 林宏明, 藤井勲, 平井嘉勝, 高津聖志
  • Organizer: 日本薬学会 第136年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-03-26
• [Presentation] Accumulation of and increased IL-1β production by neutrophils in adipose tissue: roles of free fatty acid and leukotriene B4 (2015)
  • Author(s): Yasuharu Watanabe, Yoshinori Nagai Y, Kiyoshi Takatsu
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2015-11-18
• [Presentation] Role of IL-5-producing ILC2s in T cell independent-IgA production in the large intestine (2015)
  • Author(s): Tsutomu Yanagibashi, Masashi Ikutani, Yoshinori Nagai, Kiyoshi Takatsu K
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2015-11-18
• [Presentation] 遊離脂肪酸誘発性の内臓脂肪組織炎症における好中球の機能解析 (2015)
  • Author(s): 渡邉康春, 長井良憲, 高津聖志
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-02
• [Presentation] 遊離脂肪酸誘発性の内臓脂肪組織炎症モデルにおける好中球とIL-1βの機能解析 (2015)
  • Author(s): 長井良憲, 渡邉康春, 高津聖志
  • Organizer: 第36回日本炎症・再生医学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム
  • Year and Date: 2015-07-21
• [Remarks] 富山大学大学院医学薬学研究部（医学）免疫バイオ・創薬探索研究講座 高津研究室
  • URL: http://www.med.u-toyama.ac.jp/immbio/
• [Remarks] http://www.med.u-toyama.ac.jp/immbio/index.html
• [Remarks] 富山大学大学院医学薬学研究部（医学）免疫バイオ・創薬探索研究講座 高津研究室
  • URL: http://www.med.u-toyama.ac.jp/immbio/index.html