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

• Project/Area Number: 18K08502
• 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: Chiba 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: ¥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。

Research Products

• [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 rats (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Prolyl isomerase Pin1 interacts with adipose triglyceride lipase and negatively controls both its expression and lipolysis (2021)
  • 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
  • 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 treatment (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Prolyl isomerase Pin1 in metabolic reprogramming of cancer cells (2020)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins (2019)
  • 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
  • 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 Mice (2019)
  • 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
  • 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 mice (2019)
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] Molecular Mechanisms of Hypothalamic Insulin Resistance (2019)
  • Author(s): Ono Hiraku
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 6 Pages: 1317-1317
  • DOI: 10.3390/ijms20061317
  • Peer Reviewed / Open Access
• [Journal Article] Prolyl isomerase Pin1 binds to and stabilizes acetyl CoA carboxylase 1 protein, thereby supporting cancer cell proliferation (2019)
  • 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
  • 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 diet (2019)
  • 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
  • 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
  • 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
• [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 Model (2018)
  • 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
  • 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
  • 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
  • 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
• [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
  • 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
• [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
• [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
• [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
  • 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
• [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
• [Presentation] Mechanisms and Roles of FoxO1-Akt Negative Feedback Pathway in Adipocytes (2020)
  • Author(s): Tomohiro Ohno, Hiraku Ono, Koutaro Yokote
  • Organizer: American Diabetes Association 80th Scientific Sessions
  • 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
• [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
• [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
• [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
• [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
  • 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
  • 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
• [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
• [Book] 日常診療に活かす診療ガイドラインUPDATE 肥満症 pp413-418 (2020)
  • 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
• [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