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Direct and Indirect Effects of Insulin on Target Tissues to Decrease Glucose

Research Project

Project/Area Number 18K08502
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54040:Metabolism and endocrinology-related
Research InstitutionChiba University

Principal Investigator

Ono Hiraku  千葉大学, 大学院医学研究院, 准教授 (10570616)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsインスリン / ブドウ糖 / 肥満 / 摂食 / Akt / FoxO / SGLT2 / 中枢神経 / 視床下部 / 摂食調節 / FoxO1 / 糖代謝 / 脂肪組織 / 肝臓
Outline of Final Research Achievements

Insulin and glucose are maintaining metabolic homeostasis of whole body via their signals in multiple target organs, while the precise mechanisms are unclear. We performed artificial bidirectional interventions on insulin/glucose signaling in their target tissues. Transcriptional factor FoxO1 generally antagonizes insulin signaling, because insulin inhibits its transcriptional activity. In contrast, we found that constitutive activation of FoxO1 in adipocytes rather enhances glucose uptake and lipogenesis without enhancing cell proliferation, suggesting that FoxO1 activation in adipose tissue is able to improve metabolism without a risk of tumorigenesis. Moreover, we found an inhibition of sodium-glucose cotransporter 2 (SGLT2) in the central nervous system enhances food intake, suggesting that central SGLT2 has a role to sense glucose in the brain to regulate food intake.

Academic Significance and Societal Importance of the Research Achievements

糖尿病や肥満の根治療法は未だ発見されておらず,これはインスリンが糖代謝をつかさどる仕組みや,体重が一定に維持される仕組みが未解明であるからに他ならない。本研究で見出された,脂肪組織でFoxO1を活性化させると腫瘍化のリスクなく糖代謝が改善することや,脳SGLT2が摂食調節に関与しているという知見は,新たな糖尿病や肥満の治療法を発見できる糸口になりうる成果と考えている。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (35 results)

All 2021 2020 2019 2018

All Journal Article (17 results) (of which Int'l Joint Research: 9 results,  Peer Reviewed: 15 results,  Open Access: 14 results) Presentation (15 results) (of which Int'l Joint Research: 1 results,  Invited: 4 results) Book (3 results)

  • [Journal Article] Central administration of sodium-glucose cotransporter-2 inhibitors increases food intake involving adenosine monophosphate-activated protein kinase phosphorylation in the lateral hypothalamus in healthy rats2021

    • Author(s)
      Takeda Kenji、Ono Hiraku、Ishikawa Ko、Ohno Tomohiro、Kumagai Jin、Ochiai Hidetoshi、Matumoto Ai、Yokoh Hidetaka、Maezawa Yoshiro、Yokote Koutaro
    • Journal Title

      BMJ Open Diabetes Research & Care

      Volume: 9 Issue: 1 Pages: e002104-e002104

    • DOI

      10.1136/bmjdrc-2020-002104

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prolyl isomerase Pin1 interacts with adipose triglyceride lipase and negatively controls both its expression and lipolysis2021

    • Author(s)
      Yusuke Nakatsu, Takeshi Yamamotoya, Mizuki Okumura, Tetsuhiro Ishii, Mayu Kanamoto, Miki Naito, Mikako Nakanishi, Shunya Aoyama, Yasuka Matsunaga, Akifumi Kushiyama, Hideyuki Sakoda, Midori Fujishiro, Hiraku Ono, Tomoichiro Asano
    • Journal Title

      Metabolism

      Volume: 15 Pages: 154459-154459

    • DOI

      10.1016/j.metabol.2020.154459

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Detailed analysis of lipolytic enzymes in a Japanese woman of familial lipoprotein lipase deficiency - Effects of pemafibrate treatment2020

    • Author(s)
      Minamizuka T, Kobayashi J, Tada H, Miyashita K, Koshizaka M, Maezawa Y, Ono H, Yokote K
    • Journal Title

      CLINICA CHIMICA ACTA

      Volume: 510 Pages: 216-219

    • DOI

      10.1016/j.cca.2020.07.031

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prolyl isomerase Pin1 in metabolic reprogramming of cancer cells2020

    • Author(s)
      Nakatsu Yusuke、Yamamotoya Takeshi、Ueda Koji、Ono Hiraku、Inoue Masa-Ki、Matsunaga Yasuka、Kushiyama Akifumi、Sakoda Hideyuki、Fujishiro Midori、Matsubara Akio、Asano Tomoichiro
    • Journal Title

      Cancer Letters

      Volume: 470 Pages: 106-114

    • DOI

      10.1016/j.canlet.2019.10.043

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins2019

    • Author(s)
      Inoue Masa-Ki、Nakatsu Yusuke、Yamamotoya Takeshi、Hasei Shun、Kanamoto Mayu、Naitou Miki、Matsunaga Yasuka、Sakoda Hideyuki、Fujishiro Midori、Ono Hiraku、Kushiyama Akifumi、Asano Tomoichiro
    • Journal Title

      Cells

      Volume: 8 Issue: 12 Pages: 1545-1545

    • DOI

      10.3390/cells8121545

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice2019

    • Author(s)
      Mizuno Yu、Yamamotoya Takeshi、Nakatsu Yusuke、Ueda Koji、Matsunaga Yasuka、Inoue Masa-Ki、Sakoda Hideyuki、Fujishiro Midori、Ono Hiraku、Kikuchi Takako、Takahashi Masahiro、Morii Kenichi、Sasaki Kensuke、Masaki Takao、Asano Tomoichiro、Kushiyama Akifumi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Issue: 19 Pages: 4680-4680

    • DOI

      10.3390/ijms20194680

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Possible involvement of normalized Pin1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in mice2019

    • Author(s)
      Inoue Masa-Ki、Matsunaga Yasuka、Nakatsu Yusuke、Yamamotoya Takeshi、Ueda Koji、Kushiyama Akifumi、Sakoda Hideyuki、Fujishiro Midori、Ono Hiraku、Iwashita Misaki、Sano Tomomi、Nishimura Fusanori、Morii Kenichi、Sasaki Kensuke、Masaki Takao、Asano Tomoichiro
    • Journal Title

      Diabetology & Metabolic Syndrome

      Volume: 11 Issue: 1 Pages: 57-57

    • DOI

      10.1186/s13098-019-0454-6

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 肥満症の栄養管理2019

    • Author(s)
      中野香名,野本尚子,小野啓,横手幸太郎
    • Journal Title

      臨床栄養臨時増刊号高齢者の栄養管理パーフェクトガイド

      Volume: 135 Pages: 506-512

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Molecular Mechanisms of Hypothalamic Insulin Resistance2019

    • Author(s)
      Ono Hiraku
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Issue: 6 Pages: 1317-1317

    • DOI

      10.3390/ijms20061317

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prolyl isomerase Pin1 binds to and stabilizes acetyl CoA carboxylase 1 protein, thereby supporting cancer cell proliferation2019

    • Author(s)
      Ueda Koji、Nakatsu Yusuke、Yamamotoya Takeshi、Ono Hiraku、Inoue Yuki、Inoue Masa-Ki、Mizuno Yu、Matsunaga Yasuka、Kushiyama Akifumi、Sakoda Hideyuki、Fujishiro Midori、Takahashi Shin-Ichiro、Matsubara Akio、Asano Tomoichiro
    • Journal Title

      Oncotarget

      Volume: 10 Issue: 17 Pages: 1637-1648

    • DOI

      10.18632/oncotarget.26691

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CXCL12-CXCR4 pathway activates brown adipocytes and induces insulin resistance in CXCR4-deficient mice under high-fat diet2019

    • Author(s)
      Kurita Kenichi、Ishikawa Ko、Takeda Kenji、Fujimoto Masanori、Ono Hiraku、Kumagai Jin、Inoue Hiromi、Yokoh Hidetaka、Yokote Koutaro
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 6165-6165

    • DOI

      10.1038/s41598-019-42127-8

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16.2019

    • Author(s)
      Nakatsu Y, Matsunaga Y, Yamamotoya T, Ueda K, Inoue MK, Mizuno Y, Nakanishi M, Sano T, Yamawaki Y, Kushiyama A, Sakoda H, Fujishiro M, Ryo A, Ono H, Minamino T, Takahashi SI, Ohno H, Yoneda M, Takahashi K, Ishihara H, Katagiri H, Nishimura F, Kanematsu T, Yamada T, Asano T.
    • Journal Title

      Cell Rep.

      Volume: 26 Issue: 12 Pages: 3221-3230

    • DOI

      10.1016/j.celrep.2019.02.066

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 高度肥満を認める1型糖尿病の患者2019

    • Author(s)
      小野 啓
    • Journal Title

      臨床雑誌内科 診療力を上げる!症例問題集

      Volume: 123 Pages: 999-1000

    • Related Report
      2018 Research-status Report
  • [Journal Article] The Xanthine Oxidase Inhibitor Febuxostat Suppresses the Progression of IgA Nephropathy, Possibly via Its Anti-Inflammatory and Anti-Fibrotic Effects in the gddY Mouse Model2018

    • Author(s)
      Inoue Masa-Ki、Yamamotoya Takeshi、Nakatsu Yusuke、Ueda Koji、Inoue Yuki、Matsunaga Yasuka、Sakoda Hideyuki、Fujishiro Midori、Ono Hiraku、Morii Kenichi、Sasaki Kensuke、Masaki Takao、Suzuki Yusuke、Asano Tomoichiro、Kushiyama Akifumi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 19 Issue: 12 Pages: 3967-3967

    • DOI

      10.3390/ijms19123967

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Development of Pin1 inhibitors and their potential as therapeutic agents.2018

    • Author(s)
      Nakatsu Y, Matsunaga Y, Ueda K, Yamamotoya T, Inoue Y, Inoue MK, Mizuno Y, Kushiyama A, Ono H, Fujishiro M, Ito H, Okabe T, Asano T.
    • Journal Title

      Curr Med Chem

      Volume: - Issue: 20 Pages: 1-1

    • DOI

      10.2174/0929867325666181105120911

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Gut microbiota as a therapeutic target for metabolic disorders.2018

    • Author(s)
      Okubo H, Nakatsu Y, Kushiyama A, Yamamotoya T, Matsunaga Y, Inoue MK, Fujishiro M, Sakoda H, Ohno H, Yoneda M, Ono H, Asano T.
    • Journal Title

      Curr Med Chem.

      Volume: 25 Issue: 9 Pages: 984-1001

    • DOI

      10.2174/0929867324666171009121702

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 12年にわたる内科的治療にて治療効果が不十分であり肥満外科手術を施行した2型糖尿病の症例2018

    • Author(s)
      小野 啓
    • Journal Title

      Medical Practice

      Volume: 35 Pages: 304-308

    • Related Report
      2018 Research-status Report
  • [Presentation] 腹壁蜂窩織炎の治療後,LSGにて減量を得るも余剰皮膚切除後に皮膚創離開と感染により創傷治癒遅延が生じた一例2021

    • Author(s)
      小野啓,野本尚子,岩立康男,横手幸太郎
    • Organizer
      第41回日本肥満学会・第38回日本肥満症治療学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 肥満症治療のためのセマグルチド投与に伴う体重減少と嘔気について2021

    • Author(s)
      横手幸太郎, 小野啓, Wharton Sean, Birkenfeld Andreas L, McGowan Barbara, Carson Charlotte G, Jepsen Cecilie H, Endahl Lars, Pedersen Sue D
    • Organizer
      第41回日本肥満学会・第38回日本肥満症治療学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 運動による減量に乏しい経過からKlinefelter症候群の診断に至った高度肥満症の一例2021

    • Author(s)
      佐藤愛,小野啓,落合英俊,大野友寛,武田健治,熊谷仁,林愛子,横手 幸太郎
    • Organizer
      第41回日本肥満学会・第38回日本肥満症治療学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 当院肥満外来通院1年間における内科的治療の減量効果2021

    • Author(s)
      林愛子,前澤善朗,前田祐香里,越坂理也,北原綾,小野啓,林秀樹,横手幸太郎
    • Organizer
      第41回日本肥満学会・第38回日本肥満症治療学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 内科治療の現状と今後2020

    • Author(s)
      小野啓
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 脂肪細胞におけるFoxO1-Aktフィードバック機構の機序と役割2020

    • Author(s)
      大野友寛,小野啓,濱野陽彩,佐藤愛,落合英俊,武田健治,熊谷仁,横尾英孝,前澤善朗,藤代緑,片桐秀樹,浅野知一郎,横手幸太郎
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 2型糖尿病を対象としたプリン体代謝関連物質の血管合併症発症および進展に対する影響の研究(続報)2020

    • Author(s)
      櫛山暁史,小川克彦,渡邉健太郎,江頭富士子,岡本真由美,村瀬貴代,中村敬志,赤利精悟,迫田秀之,小野啓,山本屋武,中津祐介,浅野知一郎,石原寿光
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Mechanisms and Roles of FoxO1-Akt Negative Feedback Pathway in Adipocytes2020

    • Author(s)
      Tomohiro Ohno, Hiraku Ono, Koutaro Yokote
    • Organizer
      American Diabetes Association 80th Scientific Sessions
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 脂肪細胞におけるFoxO1-Aktフィードバック機構の機序と役割2019

    • Author(s)
      大野友寛、小野啓、浜野陽彩、武田健治、藤城緑、前澤善朗、片桐秀樹、浅野知一郎、横手幸太郎
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 高度肥満症患者における性格や過食症状,不安・うつ尺度について2019

    • Author(s)
      佐藤愛,小野啓,北原綾,松本淳子,林愛子,横手幸太郎
    • Organizer
      第40回日本肥満学会・第37回日本肥満症治療学会合同学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 脂肪細胞におけるFoxO1-Aktフィードバック機構の機序と役割2018

    • Author(s)
      大野友寛, 小野啓, 横手幸太郎
    • Organizer
      第39回日本肥満学会
    • Related Report
      2018 Research-status Report
  • [Presentation] 肝臓および脂肪組織におけるFoxO1-Aktフィードバック機構の機序と役割2018

    • Author(s)
      大野友寛, 小野啓, 濱野陽彩, 武田武治, 栗田健市, 藤城緑, 石川耕, 前澤善朗, 片桐秀樹, 浅野知一郎, 横手幸太郎
    • Organizer
      第55回臨床分子医学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 高度肥満症専門外来における治療法の選択と予後;千葉大学におけるチーム医療2018

    • Author(s)
      小野 啓
    • Organizer
      第39回日本肥満学会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 県民公開シンポジウム「メタボで何が悪い!?」2018

    • Author(s)
      小野 啓
    • Organizer
      千葉県医師会医学会第19回学術大会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 脂肪組織におけるFoxO1-Aktフィードバック機構の機序と役割2018

    • Author(s)
      大野 友寛、小野 啓、浜野 陽彩、武田 健治、藤城 緑、石川 耕、前澤 善朗、片桐 秀樹、浅野 知一郎、横手 幸太郎
    • Organizer
      第23回アディポサイエンス・シンポジウム
    • Related Report
      2018 Research-status Report
  • [Book] 今日の治療指針 2021年版2021

    • Author(s)
      小野啓(分担執筆)
    • Total Pages
      2192
    • Publisher
      医学書院
    • ISBN
      9784260042826
    • Related Report
      2020 Annual Research Report
  • [Book] 日常診療に活かす診療ガイドラインUPDATE 肥満症 pp413-4182020

    • Author(s)
      佐藤愛,小野啓,横手幸太郎
    • Total Pages
      1060
    • Publisher
      メディカルレビュー社
    • ISBN
      9784779222535
    • Related Report
      2019 Research-status Report
  • [Book] 第三期 特定健診・特定保健指導ガイド2018

    • Author(s)
      門脇孝,津下一代,永井良三,多田羅浩三,西沢均,下村伊一郎,小野啓,横手幸太郎,崔仁哲,磯博康,鈴木隆雄,鈴木亮,佐藤大,加藤秀樹,南学正臣,三浦克之,高本偉碩,寺本民生,岡村友教,宮本恵宏,中川詩織,安田宜成,和田隆志,小久保喜弘,峰松一夫,川崎良,中山健夫,杉田由加里,武見ゆかり,林芙美,中田由夫,中村正和,他
    • Total Pages
      328
    • Publisher
      南山堂
    • ISBN
      9784525207816
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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