Functional analysis of TRIF-mediated innate immune signaling in hypothalamic inflammation-induced dysregulation of food intake

• Project/Area Number: 19K09019
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Toyama Prefectural Institute for Pharmaceutical Research
• Principal Investigator: Watanabe Yasuharu 富山県薬事総合研究開発センター, その他部局等, 主任研究員 (80646307)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 視床下部炎症 / 自然免疫 / 肥満 / 自然免疫センサー / 炎症 / 過食

Outline of Research at the Start

高脂肪食によって誘導される脳の自律神経中枢である視床下部の炎症反応が、摂食抑制ホルモンであるレプチンのシグナルを障害し、過食になることが肥満のメカニズムの１つとして注目されている。我々は、自然免疫センサーのシグナル伝達分子TRIFが視床下部炎症に関与し、摂食調整異常を誘導して、過食性肥満の発症に深く関与することを見出した。
そこで本研究では、TRIFシグナルによる視床下部炎症の誘導機序を解明し、過食の新規分子メカニズムを明らかにする。

Outline of Final Research Achievements

Recent accumulating evidence suggests that toll like receptor 4 (TLR4) and the adaptor protein MyD88 induce hypothalamic inflammation, which inhibits leptin-induced anorexia and promotes hyperphagia, obesity, and metabolic syndrome.
We found that TLR4-MyD88- and TLR3-independent TLR adaptor protein TRIF signaling pathway was involved in high-fat diet (HFD)-induced hypothalamic inflammation and hyperphagia. TRIF-dependent STING singling, adaptor protein in the cytosolic DNA sensing pathway, induced hypothalamic inflammation and impaired leptin singling in hypothalamus. These results suggested that STING-TRIF singling contributes of hypothalamic inflammation and leptin resistance under HFD treatment.

Academic Significance and Societal Importance of the Research Achievements

これまで考えられているTLR4-MyD88B経路よりもSTING-TRIFシグナル経路が、視床下部炎症に深く関与することを見出した。今後STING-TRIFシグナルを誘導する上流分子や責任細胞の同定により、摂食調節異常の新規メカニズムを提唱でき、自制が困難な過食性肥満の解明に貢献できると考える。

Research Products

• [Journal Article] Betulin Attenuates TGF-β1- and PGE₂-Mediated Inhibition of NK Cell Activity to Suppress Tumor Progression and Metastasis in Mice (2022)
  • Author(s): Ogasawara Masaru、Yamasaki-Yashiki Shino、Hamada Masahiro、Yamaguchi-Miyamoto Tomomi、Kawasuji Toru、Honda Hiroe、Yanagibashi Tsutomu、Ikutani Masashi、Watanabe Yasuharu、Fujimoto Ryota、Matsunaga Takayuki、Nakajima Noriyuki、Nagai Yoshinori、Takatsu Kiyoshi
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 45 Issue: 3 Pages: 339-353
  • DOI: 10.1248/bpb.b21-00921
  • NAID: 130008165815
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2022-03-01
  • Peer Reviewed / Open Access
• [Journal Article] Isoliquiritigenin Attenuates Adipose Tissue Inflammation and Metabolic Syndrome by Modifying Gut Bacteria Composition in Mice (2022)
  • Author(s): Ishibashi Riko、Furusawa Yukihiro、Honda Hiroe、Watanabe Yasuharu、Fujisaka Shiho、Nishikawa Miyu、Ikushiro Shinichi、Kurihara Shin、Tabuchi Yoshiaki、Tobe Kazuyuki、Takatsu Kiyoshi、Nagai Yoshinori
  • Journal Title: Molecular Nutrition & Food Research Volume: - Issue: 10 Pages: 2101119-2101119
  • DOI: 10.1002/mnfr.202101119
  • Peer Reviewed / Open Access
• [Journal Article] Bone marrow transplantation into Abcd1‐deficient mice: Distribution of donor derived‐cells and biological characterization of the brain of the recipient mice (2021)
  • Author(s): Morita Masashi、Kaizawa Taro、Yoda Taiki、Oyama Takuro、Asakura Reina、Matsumoto Shun、Nagai Yoshinori、Watanabe Yasuharu、Watanabe Shiro、Kobayashi Hiroshi、Kawaguchi Kosuke、Yamamoto Seiji、Shimozawa Nobuyuki、So Takanori、Imanaka Tsuneo
  • Journal Title: Journal of Inherited Metabolic Disease Volume: 44 Issue: 3 Pages: 718-727
  • DOI: 10.1002/jimd.12346
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bidirectional Crosstalk Between Neutrophils and Adipocytes Promotes Adipose Tissue Inflammation (2019)
  • Author(s): Watanabe Y, Nagai Y, Honda H, Okamoto N, Yanagibashi T, Ogasawara M, Yamamoto S, Imamura R, Takasaki I, Hara H, Sasahara M, Arita M, Hida S, Taniguchi S, Suda T, Takatsu K.
  • Journal Title: FASEB J. Volume: 33(11) Issue: 11 Pages: 11821-11835
  • DOI: 10.1096/fj.201900477rr
  • Peer Reviewed / Open Access
• [Presentation] イソリクイリチゲニンによる腸内細菌叢の変動を介したメタボリックシンドロームの改善 (2022)
  • Author(s): 石橋璃子, 古澤之裕, 本田裕恵, 渡邉康春, 藤坂志帆, 戸邉一之, 高津聖志, 栗原新, 田渕圭章, 長井良憲
  • Organizer: 日本薬学会第142年会
• [Presentation] Crosstalk between neutrophils and adipocytes exacerbates adipose tissue inflammation in progression of type 2 diabetes (2021)
  • Author(s): 渡邉康春
  • Organizer: 第6回富山バーゼルジョインシンポジウム
  • Int'l Joint Research / Invited
• [Presentation] Bidirectional crosstalk between neutrophils and adipocytes promotes adipose tissue inflammation (2020)
  • Author(s): Watanabe Y., Nagai Y.,and Takatsu K
  • Organizer: The 104th Annual Meeting of The American Association of Immunologists
  • Int'l Joint Research
• [Presentation] TLRのアダプター分子TRIFを介した摂食調節異常・視床下部炎症の解析 (2019)
  • Author(s): 渡邉康春、長井良憲、 髙津聖志
  • Organizer: 第40回日本炎症・再生医学会
• [Presentation] 内臓脂肪組織炎症における好中球と脂肪細胞のクロストーク (2019)
  • Author(s): 長井良憲、渡邉康春、髙津聖志
  • Organizer: 第40回日本炎症・再生医学会
• [Presentation] 好中球と脂肪細胞の相互作用は内臓脂肪組織の炎症を誘導する (2019)
  • Author(s): 渡邉康春、長井良憲、髙津聖志
  • Organizer: 第92回日本生化学会大会
• [Remarks] 富山県薬事総合研究開発センター
  • URL: https://www.pref.toyama.jp/1285/kurashi/kenkou/iryou/1285/index.html