Free fatty acids-mediated dynamic changes of neutrophils induce adipose tissue inflammation

• Project/Area Number: 16K19532
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: University of Toyama
• Principal Investigator: Watanabe Yasuharu 富山大学, 大学院医学薬学研究部(医学), 客員准教授 (80646307)
• Research Collaborator: NAGAI Yoshinori 富山県立大学, 工学部, 教授 (30431761)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 好中球 / 脂肪細胞 / IL-1 beta / 内臓脂肪組織 / 炎症 / 脂肪組織 / 脂肪酸

Outline of Final Research Achievements

Obesity-associated adipose tissue inflammation contributes to the development of type 2 diabetes. In obese adipose tissue, free fatty acids (FFAs) are released from hypertrophied adipocytes and considered as trigger for adipose tissue inflammation by recruiting immune cells including macrophages. In this study, we found that FFAs induce the infiltration of neutrophils into adipose tissue via LTB4 production from adipose tissue. Infiltrated neutrophils interacted with adipocytes and increased pro-IL-1 beta expression through NF-kappa B pathway activation. IL-1 beta was produced from neutrophils and induced S100A8 production from adipocytes, which promoted macrophage infiltration into adipose tissue and exacerbated the inflammation. We have provided novel insights related to adipose tissue neutrophils and IL-1 beta, and dissected their roles in the initiation of adipose tissue inflammation.

Academic Significance and Societal Importance of the Research Achievements

研究代表者は、遊離脂肪酸の増加が1つのトリガーとなり、好中球がVATに浸潤し、脂肪細胞と相互作用することによりVAT炎症やマクロファージの浸潤に関与する一連のVAT炎症の誘導機序を見出した。本研究により、好中球はマクロファージよりも早期のVAT炎症に大きく寄与していることから、好中球は2型糖尿病の予防薬や機能性食品のターゲットの１つになりうることが示唆された。

Research Products

• [Journal Article] 肥満に伴う内臓脂肪組織炎症とメタボリック症候群における好中球の役割 (2018)
  • Author(s): 渡邉康春、長井良憲、髙津聖志
  • Journal Title: 臨床免疫・アレルギー科 Volume: ６９ Pages: 434-441
• [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] 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] 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
• [Presentation] 遊離脂肪酸を起点とした好中球と脂肪細胞との相互作用は、IL-1β産生とマクロファージの内臓脂肪組織浸潤に関与する (2018)
  • Author(s): 渡邉康春, 長井良憲, 高津聖志
  • Organizer: 第39回日本炎症・再生医学会
• [Presentation] Crosstalk between neutrophils and adipocytes exacerbates adipose tissue inflammation in progression of type 2 diabetes (2018)
  • Author(s): 渡邉康春, 長井良憲, 高津聖志
  • Organizer: 第5回富山・バーゼル医薬品研究開発シンポジウム
• [Presentation] The exploration of natural products as inhibitors of obesity-associated adipose tissue inflammation (2018)
  • Author(s): 渡邉康春
  • Organizer: The Virtual University of Pakistan:International Conference on "Therapeutic Importance of Traditional medicine”
  • Int'l Joint Research / Invited
• [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] The interaction of neutrophils with adipocytes plays a key role in the infiltration of macrophage into the adipose tissue (2017)
  • Author(s): Watanabe Yasuharu, Nagai Yoshinori, Takatsu Kiyoshi
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Adipose tissue neutrophils are primed by the interaction with adipocytes (2016)
  • Author(s): Watanabe Yasuharu, Nagai Yoshinori, Takatsu Kiyoshi
  • 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・ラグナガーデンホテル(沖縄県宜野湾市)
  • 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(東京都江東区）
  • 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(富山県富山市)
  • 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(京都府京都市)
  • Year and Date: 2016-06-16
• [Presentation] 骨髄移植による副腎白質ジストロフィー 発症抑制機構の解明：レシピエントマウスの生化学的解析 (2016)
  • Author(s): 大山拓郎、冨田勇、螺澤太郎、松本隼、守田雅志、渡辺志朗、渡邉康春、長井良憲、高津聖志、山本誠二、石井陽子、笹原正清、今中常雄
  • Organizer: 第128回薬学会北陸支部会
  • Place of Presentation: 北陸大学(石川県金沢市）
• [Book] Biological activities and action mechanisms of licorice ingredients (2017)
  • Author(s): Nagai Y, Watanabe Y, Honda H, Takatsu K
  • Total Pages: 172
  • Publisher: InTech
  • ISBN: 9789535131205
• [Book] Chronic Inflammation: Mechanisms and Regulation (2016)
  • Author(s): Nagai Y, Honda H, Watanabe Y, Takatsu K
  • Total Pages: 702
  • Publisher: Springer Japan
• [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 髙津研究室
  • URL: http://www.med.u-toyama.ac.jp/immbio/index.html
• [Remarks] 富山大学大学院医学薬研究部(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