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Pathological Significance of TREM2 in Obesity/Diabetes-Related Cognitive Impairment through the Brain-Adipose Tissue Axis

Research Project

Project/Area Number 19K07927
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52010:General internal medicine-related
Research InstitutionHealth Science University

Principal Investigator

TANAKA Masashi  健康科学大学, 健康科学部, 教授 (60381167)

Co-Investigator(Kenkyū-buntansha) 浅原 哲子 (佐藤哲子)  独立行政法人国立病院機構(京都医療センター臨床研究センター), 内分泌代謝高血圧研究部, 研究部長 (80373512)
猪原 匡史  国立研究開発法人国立循環器病研究センター, 病院, 部長 (00372590)
Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsTREM2 / ミクログリア / 認知症 / 炎症 / 糖尿病 / 肥満 / 単球 / 血管合併症 / 脳アミロイド血管症 / タキシフォリン
Outline of Research at the Start

超高齢社会が進む本邦では、特に高齢者における肥満・糖尿病の増加とともに認知症が急増し、その対策は急務である。本研究では、GWASから認知症との関与が示唆される細胞表面分子・TREM2に焦点を当て、肥満・糖尿病の脂肪組織における病態意義と認知機能低下における病態意義を検討する。さらに、植物由来生理活性物質・タキシフォリンによる糖代謝悪化・認知機能低下の改善作用の詳細と分子機構を明らかにする。以上より、肥満・糖尿病に伴う認知症の新規予知・治療戦略の開発を目指す。

Outline of Final Research Achievements

The present study demonstrated novel suppressive effects of bioactive molecule taxifolin and peptide hormone oxytocin on microglial activation. Furthermore, our longitudinal study showed that serum sTREM2 levels would be a potential novel marker for predicting cognitive impairment in type 2 diabetes, using a database of a multicenter prospective observational cohort study including patients with obesity and/or diabetes. These findings could help develop novel predictive markers and effective therapeutic strategies for cognitive impairment in patients with diabetes.

Academic Significance and Societal Importance of the Research Achievements

本研究により、脳保護におけるタキシフォリンとオキシトシンの新規機能的意義が明らかとなり、認知機能低下抑制のための新たな介入の可能性が見出された。また、糖尿病患者の血清sTREM2を検討することで、将来的な認知機能低下のリスクを予測できる可能性が示され、血清sTREM2の新たな臨床的意義が明らかとなった。これらの成果は、糖尿病に伴う認知機能低下の新規予知指標・治療戦略の構築に貢献できると考えられる。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (30 results)

All 2023 2022 2021 2020 2019

All Journal Article (19 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 14 results,  Open Access: 14 results) Presentation (11 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results)

  • [Journal Article] Novel Therapeutic Potentials of Taxifolin for Obesity-Induced Hepatic Steatosis, Fibrogenesis, and Tumorigenesis2023

    • Author(s)
      Inoue Takayuki、Fu Bin、Nishio Miwako、Tanaka Miyako、Kato Hisashi、Tanaka Masashi、Itoh Michiko、Yamakage Hajime、Ochi Kozue、Ito Ayaka、Shiraki Yukihiro、Saito Satoshi、Ihara Masafumi、Nishimura Hideo、Kawamoto Atsuhiko、Inoue Shian、Saeki Kumiko、Enomoto Atsushi、Suganami Takayoshi、Satoh-Asahara Noriko
    • Journal Title

      Nutrients

      Volume: 15 Issue: 2 Pages: 350-350

    • DOI

      10.3390/nu15020350

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Soluble TREM2 and Alzheimer-related biomarker trajectories in the blood of patients with diabetes based on their cognitive status2022

    • Author(s)
      Satoh-Asahara Noriko、Yamakage Hajime、Tanaka Masashi、Kawasaki Teruaki、Matsuura Sayo、Tatebe Harutsugu、Akiguchi Ichiro、Tokuda Takahiko
    • Journal Title

      Diabetes Research and Clinical Practice

      Volume: 193 Pages: 110121-110121

    • DOI

      10.1016/j.diabres.2022.110121

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases2022

    • Author(s)
      Saito Satoshi、Ono Kenjiro、Tanaka Masashi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 18 Pages: 10275-10275

    • DOI

      10.3390/ijms231810275

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Higher Serum Soluble TREM2 as a Potential Indicative Biomarker for Cognitive Impairment in Inadequately Controlled Type 2 Diabetes Without Obesity: The DOR-KyotoJ-12022

    • Author(s)
      Tanaka Masashi、Yamakage Hajime、Satoh-Asahara Noriko、et al
    • Journal Title

      Frontiers in Endocrinology

      Volume: 13 Pages: 880148-880148

    • DOI

      10.3389/fendo.2022.880148

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 筋肉関係(ミオスタチン)2021

    • Author(s)
      浅原哲子、山陰一、井上隆之、田中将志
    • Journal Title

      腎と透析

      Volume: 91 Pages: 541-546

    • Related Report
      2021 Research-status Report
  • [Journal Article] 腸-脳-筋連関による認知症・サルコペニア進展機序の解明を目指して2021

    • Author(s)
      田中将志、山陰一、浅原哲子
    • Journal Title

      循環器内科

      Volume: 90 Pages: 347-353

    • NAID

      40022697796

    • Related Report
      2021 Research-status Report
  • [Journal Article] 摂食・飲水制限による急速減量におけるタンパク質分解2021

    • Author(s)
      長谷川和哉、田中将志
    • Journal Title

      アグリバイオ

      Volume: 5 Pages: 98-101

    • NAID

      40022631948

    • Related Report
      2021 Research-status Report
  • [Journal Article] TREM22021

    • Author(s)
      浅原哲子、田中将志、山陰一、井上隆之
    • Journal Title

      老年内科

      Volume: 3 Pages: 739-748

    • NAID

      40022630992

    • Related Report
      2021 Research-status Report
  • [Journal Article] Potential Genetic Contributions of the Central Nervous System to a Predisposition to Elite Athletic Traits: State-of-the-Art and Future Perspectives2021

    • Author(s)
      Kitazawa Hiroya、Hasegawa Kazuya、Aruga Daichi、Tanaka Masashi
    • Journal Title

      Genes

      Volume: 12 Issue: 3 Pages: 371-371

    • DOI

      10.3390/genes12030371

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Taxifolin: A Potential Therapeutic Agent for Cerebral Amyloid Angiopathy2021

    • Author(s)
      Saito Satoshi、Tanaka Masashi、Satoh-Asahara Noriko、Carare Roxana Octavia、Ihara Masafumi
    • Journal Title

      Frontiers in Pharmacology

      Volume: 12 Pages: 643357-643357

    • DOI

      10.3389/fphar.2021.643357

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differential roles of VPS and RAAS in water homeostasis and a risk for kidney dysfunction in rats undergoing rapid fasting/dehydration with regular exercise2021

    • Author(s)
      Hasegawa KazuyA、Yamaguchi Yuya、Tanaka Masashi
    • Journal Title

      Physiological Reports

      Volume: 9 Issue: 1

    • DOI

      10.14814/phy2.14670

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 急速減量におけるタンパク質分解2021

    • Author(s)
      長谷川和哉、田中将志
    • Journal Title

      細胞

      Volume: 53 Pages: 44-46

    • NAID

      40022520035

    • Related Report
      2020 Research-status Report
  • [Journal Article] Beneficial Effects of Ipragliflozin on the Renal Function and Serum Uric Acid Levels in Japanese Patients with Type 2 Diabetes: A Randomized, 12-week, Open-label, Active-controlled Trial2020

    • Author(s)
      Tanaka Masashi、Yamakage Hajime、Inoue Takayuki、Odori Shinji、Kusakabe Toru、Shimatsu Akira、Satoh-Asahara Noriko
    • Journal Title

      Internal Medicine

      Volume: 59 Issue: 5 Pages: 601-609

    • DOI

      10.2169/internalmedicine.3473-19

    • NAID

      130007804618

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2020-03-01
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Differential effects of sodium-glucose cotransporter 2 inhibitor and low-carbohydrate diet on body composition and metabolic profile in obese diabetic db/db mice2020

    • Author(s)
      Kusakabe Toru、Yokota Shigefumi、Shimizu Mika、Inoue Takayuki、Tanaka Masashi、Ohue-Kitano Ryuji、Muranaka Kazuya、Yamakage Hajime、Wada Hiromichi、Hasegawa Koji、Satoh-Asahara Noriko
    • Journal Title

      BMJ Open Diabetes Research & Care

      Volume: 8 Issue: 1 Pages: e001303-e001303

    • DOI

      10.1136/bmjdrc-2020-001303

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Potential Therapeutic Approaches for Cerebral Amyloid Angiopathy and Alzheimer’s Disease2020

    • Author(s)
      Tanaka Masashi、Saito Satoshi、Inoue Takayuki、Satoh-Asahara Noriko、Ihara Masafumi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 6 Pages: 1992-1992

    • DOI

      10.3390/ijms21061992

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of dapagliflozin on the serum levels of fibroblast growth factor?21 and myokines and muscle mass in Japanese patients with type?2 diabetes: A randomized, controlled trial2019

    • Author(s)
      Yamakage Hajime、Tanaka Masashi、Inoue Takayuki、Odori Shinji、Kusakabe Toru、Satoh‐Asahara Noriko
    • Journal Title

      Journal of Diabetes Investigation

      Volume: none Issue: 3 Pages: 653-661

    • DOI

      10.1111/jdi.13179

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Oxytocin Suppresses Inflammatory Responses Induced by Lipopolysaccharide through Inhibition of the eIF-2α?ATF4 Pathway in Mouse Microglia2019

    • Author(s)
      Inoue Takayuki、Yamakage Hajime、Tanaka Masashi、Kusakabe Toru、Shimatsu Akira、Satoh-Asahara Noriko
    • Journal Title

      Cells

      Volume: 8 Issue: 6 Pages: 527-527

    • DOI

      10.3390/cells8060527

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel Therapeutic Potentials of Taxifolin for Amyloid-β-associated Neurodegenerative Diseases and Other Diseases: Recent Advances and Future Perspectives2019

    • Author(s)
      Tanaka Masashi、Saito Satoshi、Inoue Takayuki、Satoh-Asahara Noriko、Ihara Masafumi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Issue: 9 Pages: 2139-2139

    • DOI

      10.3390/ijms20092139

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy2019

    • Author(s)
      Inoue Takayuki、Saito Satoshi、Tanaka Masashi、Yamakage Hajime、Kusakabe Toru、Shimatsu Akira、Ihara Masafumi、Satoh-Asahara Noriko
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 116 Issue: 20 Pages: 10031-10038

    • DOI

      10.1073/pnas.1901659116

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] イメグリミンはオートファジー・ULK1を介してミクログリアにおける高グルコース誘導性炎症を抑制する2023

    • Author(s)
      加藤 久詞、岩佐 真代、岩下 香里、田中 将志、浅原 哲子
    • Organizer
      第26回アディポサイエンス・シンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] 植物由来フラボノイド・タキシフォリンは肥満・脂肪肝/NASH を改善させる2022

    • Author(s)
      加藤 久詞、Bin Fu、山陰 一、村中 和哉、岩下 香里、岩佐 真代、加藤 さやか、田中 将志、田中 都、西尾 美和子、菅波 孝祥、浅原 哲子
    • Organizer
      第43回 日本肥満学会 第40回 日本肥満症治療学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 糖尿病の認知機能低下におけるTREM2の病態意義2022

    • Author(s)
      田中 将志、山陰 一、岩下 香里、岩佐 真代、浅原 哲子
    • Organizer
      第22回日本抗加齢医学会総会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 認知症・心血管病の早期評価系構築のための多施設共同大規模肥満症コホート研究2021

    • Author(s)
      山陰一, 田中将志, 井上隆之, 村中和哉, 和田啓道, 長谷川浩二, 日下部徹, JOMS/J-DOS Study Group, 浅原哲子
    • Organizer
      第41回日本肥満学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 認知症発症予知マーカー・TREM2の肥満・脂肪組織における病態生理学的意義の検討2021

    • Author(s)
      井上隆之, 田中将志, 山陰一, 村中和哉, 日下部徹, 浅原哲子
    • Organizer
      第41回日本肥満学会
    • Related Report
      2020 Research-status Report
  • [Presentation] Taxifolin is a novel therapeutic agent for Alzheimer’s disease and cerebral amyloid angiopathy2020

    • Author(s)
      Satoshi Saito, Masashi Tanaka, Noriko Satoh-Asahara, Roxana O. Carare, Roy O. Weller, Masafumi Ihara
    • Organizer
      Alzheimer's Association International Conference
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Taxifolin is a novel therapeutic agent for cerebral amyloid angiopathy2020

    • Author(s)
      Satoshi Saito, Masashi Tanaka, Noriko Satoh-Asahara, Roxana O Carare1, and Masafumi Ihara
    • Organizer
      121st Meeting of the British Neuropathological Society
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 脂肪組織における認知症発症予知因子・TREM2 の病態生理学的意義の解明2019

    • Author(s)
      井上隆之, 田中将志, 山陰一, 村中和哉, 日下部徹, 浅原哲子
    • Organizer
      第40回日本肥満学会
    • Related Report
      2019 Research-status Report
  • [Presentation] 生活習慣病における新規認知症予知バイオマーカー候補・sTREM2 の臨床的意義の検討2019

    • Author(s)
      山陰一, 田中将志, 井上隆之, 村中和哉, 和田啓道, 長谷川浩二, 日下部徹, 浅原哲子
    • Organizer
      第40回日本肥満学会
    • Related Report
      2019 Research-status Report
  • [Presentation] 肥満糖尿病モデル動物において低炭水化物食とSGLT2 阻害薬が体組成および糖脂質代謝に及ぼす影響2019

    • Author(s)
      日下部徹, 横田繁史, 清水美佳, 井上隆之, 田中将志, 北野隆司, 山陰一, 浅原哲子
    • Organizer
      第40回日本肥満学会
    • Related Report
      2019 Research-status Report
  • [Presentation] 生活習慣病における新規認知症予知バイオマーカー候補・sTREM2の臨床的意義の検討2019

    • Author(s)
      浅原哲子, 山陰一, 田中将志, 井上隆之, 村中和哉, 和田啓道, 日下部徹, 長谷川浩二, 笠原正登
    • Organizer
      第42回日本高血圧学会総会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2024-01-30  

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