Understanding the role of disorder of vagus function in lifestyle-related diseases

• Project/Area Number: 18KT0020
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Complex Systems Disease Theory
• Research Institution: Kanazawa University
• Principal Investigator: Inoue Hiroshi 金沢大学, 新学術創成研究機構, 教授 (50397832)
• Project Period (FY): 2018-07-18 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2020: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: 生活習慣病 / 迷走神経 / 肝臓 / 臓器連関

Outline of Final Research Achievements

Nonalcoholic steatohepatitis (NASH), which occurs in association with insulin resistance and hepatic fat accumulation, confers high risk of liver fibrosis and chronic liver injury. In this study, using systemic α7 nicotinic acetylcholine receptor (A7nAchR) knockout mice (A7KO), we investigated the role of A7nAchR in NASH. Specifically, A7KO mice were fed an atherogenic high-fat diet (AD), which induce NASH. Hepatic triglyceride accumulation and elevated plasma transaminase levels were observed in AD mice, and we found the plasma transaminase level increase was higher in A7KO mice than in control mice. A7KO mice fed an AD showed significant upregulation of fibrosis-related genes and proinflammatory-cytokine genes in the liver. Histological analysis with Sirius red revealed that AD exacerbated liver fibrosis in A7KO mice. From these findings, it is clear that A7nAchR deficiency exacerbates hepatitis and fibrosis due to hepatic fat accumulation.

Academic Significance and Societal Importance of the Research Achievements

本研究からα7型ニコチン受容体(A7nAchR)が、非アルコール性脂肪肝炎(NASH)の新規な予防・治療薬候補であることを見出した。しかし、A7nAchRは中枢神経作用に多く発現しており、A7nAchRアゴニストの中枢神経作用はNASH治療薬としての妨げとなる可能性がある。NASH予防・治療へのA7nAchR活性化の応用には、肝臓以外の臓器におけるA7nAchR作用の更なる解析と、アゴニストの肝臓特異的なドラッグデリバリー法の開発が必要であると考えられた。

Research Products

• [Int'l Joint Research] University of Southern Denmark(デンマーク)
• [Int'l Joint Research] University of Southern Denmark(デンマーク)
• [Journal Article] Diet intake control is indispensable for the gluconeogenic response to sodium-glucose cotransporter 2 inhibition in male mice (2021)
  • Author(s): Hashiuchi E, Watanabe H, Kimura K, Matsumoto M, Inoue H, Inaba Y
  • Journal Title: Journal of Diabetes Investigation Volume: 12 Issue: 1 Pages: 35-47
  • DOI: 10.1111/jdi.13319
  • Peer Reviewed / Open Access
• [Journal Article] Trans-omic analysis reveals obesity-associated dysregulation of inter-organ metabolic cycles between the liver and skeletal muscle (2021)
  • Author(s): Egami Riku、Kokaji Toshiya、Hatano Atsushi、et al.
  • Journal Title: iScience Volume: 24 Issue: 3 Pages: 102217-102217
  • DOI: 10.1016/j.isci.2021.102217
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GCN2 regulates pancreatic β-cell mass by sensing intracellular amino acid levels. (2020)
  • Author(s): Kanno A, Asahara SI, Furubayashi A, Masuda K, Yoshitomi R, Suzuki E, Takai T, Kimura-Koyanagi M, Matsuda T, Bartolome A, Hirota Y, Yokoi N, Inaba Y, Inoue H, Matsumoto M, Inoue K, Abe T, Wei FY, Tomizawa K, Ogawa W, Seino S, Kasuga M, Kido Y.
  • Journal Title: JCI Insight. Volume: 5 Issue: 9 Pages: 128820-128820
  • DOI: 10.1172/jci.insight.128820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hollow fiber-combined glucose-responsive gel technology as an in vivo electronics-free insulin delivery system. (2020)
  • Author(s): Matsumoto A, Kuwata H, Kimura S, Matsumoto H, Ochi K, Moro-oka Y, Watanabe A, Yamada H, Ishii H, Miyazawa T, Chen S, Baba T, Yoshida H, Nakamura T, Inoue H, Ogawa Y, Tanaka M, Miyahara Y, Suganami T.
  • Journal Title: Commun. Biol. Volume: 3 Issue: 1 Pages: 313-313
  • DOI: 10.1038/s42003-020-1026-x
  • Peer Reviewed / Open Access
• [Journal Article] Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity (2020)
  • Author(s): Kokaji Toshiya、Hatano Atsushi、Ito Yuki、et al.
  • Journal Title: Science Signaling Volume: 13 Issue: 660 Pages: 1236-1236
  • DOI: 10.1126/scisignal.aaz1236
  • Peer Reviewed / Open Access
• [Journal Article] MAPK Erk5 in leptin receptor-expressing neurons controls body weight and systemic energy homeostasis in female mice. (2019)
  • Author(s): Horie T, Park G, Inaba Y, Hashiuchi E, Iezaki T, Tokumura K, Fukasawa K, Yamada T, HiraiwaM, Kitaguchi Y, Kamada H, Kaneda K, Tanaka T, Inoue H, Hinoi E.
  • Journal Title: Endocrinology Volume: 160 Issue: 12 Pages: 2837-2848
  • DOI: 10.1210/en.2019-00090
  • Peer Reviewed / Open Access
• [Journal Article] Hepatic gluconeogenic response to single and long-term SGLT2 inhibition in lean/obese male hepatic G6pc-reporter mice. (2019)
  • Author(s): Inaba Y, Hashiuchi E, Watanabe H, Kimura K, Sato M, Kobayashi M, Matsumoto M, Kitamura T, Kasuga M, Inoue H.
  • Journal Title: Endocrinology Volume: 160 Issue: 12 Pages: 2811-2824
  • DOI: 10.1210/en.2019-00422
  • Peer Reviewed
• [Journal Article] Logical design of oral glucose ingestion pattern minimizing blood glucose in humans. (2019)
  • Author(s): Fujii M, Murakami Y, Karasawa Y, Sumitomo Y, Fujita S, Koyama M, Uda S, Kubota H, Inoue H, Konishi K, Oba S, Ishii S, Kuroda S.
  • Journal Title: NPJ Syst Biol Appl. Volume: 5 Issue: 1 Pages: 31-31
  • DOI: 10.1038/s41540-019-0108-1
  • NAID: 120006939199
  • Peer Reviewed / Open Access
• [Journal Article] Nicotinic alpha‐7 acetylcholine receptor deficiency exacerbates hepatic inflammation and fibrosis in a mouse model of non‐alcoholic steatohepatitis (2019)
  • Author(s): Kimura Kumi、Inaba Yuka、Watanabe Hitoshi、Matsukawa Toshiya、Matsumoto Michihiro、Inoue Hiroshi
  • Journal Title: Journal of Diabetes Investigation Volume: 10 Issue: 3 Pages: 659-666
  • DOI: 10.1111/jdi.12964
  • Peer Reviewed / Open Access
• [Journal Article] 肝臓SIRT2活性の低下が肥満・2型糖尿病モデルでの肝臓糖取り込み障害を引き起こす (2019)
  • Author(s): 井上啓
  • Journal Title: Diabetes Update Volume: 8 Pages: 14-17
• [Journal Article] Dietary mung bean protein reduces high-fat diet-induced weight gain by modulating host bile acid metabolism in a gut microbiota-dependent manner. (2018)
  • Author(s): Nakatani A, Li X, Miyamoto J, Igarashi J, Watanabe H, Sutou A, Watanabe K, Motoyama T, Tachibana N, Kohno M, Inoue H, Kimura I.
  • Journal Title: Biochem Biophys Res Commun. Volume: 501 Issue: 4 Pages: 955-961
  • DOI: 10.1016/j.bbrc.2018.05.090
  • Peer Reviewed / Open Access
• [Journal Article] Dietary soybean protein ameliorates high-fat diet-induced obesity by modifying the gut microbiota-dependent biotransformation of bile acids. (2018)
  • Author(s): Watanabe K, Igarashi M, Li X, Nakatani A, Miyamoto J, Inaba Y, Sutou A, Saito T, Sato T, Tachibana N, Inoue H, Kimura I.
  • Journal Title: PLoS One. Volume: 13 Issue: 8 Pages: e0202083-e0202083
  • DOI: 10.1371/journal.pone.0202083
  • Peer Reviewed / Open Access
• [Journal Article] PHD3 regulates glucose metabolism by suppressing stress-induced signalling and optimising gluconeogenesis and insulin signalling in hepatocytes. (2018)
  • Author(s): Yano H, Sakai M, Matsukawa T, Yagi T, Naganuma T, Mitsushima M, Iida S, Inaba Y, Inoue H, Unoki-Kubota H, Kaburagi Y, Asahara S, Kido Y, Minami S, Kasuga M, Matsumoto M.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 14290-14290
  • DOI: 10.1038/s41598-018-32575-z
  • NAID: 120006529679
  • Peer Reviewed / Open Access
• [Presentation] Role of Brain-liver cross-talk in glucose homeostasis and its deterioration (2021)
  • Author(s): 井上啓
  • Organizer: 第98回日本生理学会大会
  • Invited
• [Presentation] 臓器連関と肥満 (2021)
  • Author(s): 井上啓
  • Organizer: 第41回日本肥満学会・第38回日本肥満症治療学会
  • Invited
• [Presentation] Hepatic gluconeogenic response to SGLT2 inhibition in hepatic G6pc-reporter mice with NAFLD (2020)
  • Author(s): Hashiuchi E, Inaba Y, Inoue H
  • Organizer: The Keystone Symposium on Obesity and NAFLD
  • Int'l Joint Research
• [Presentation] Investigation of a preventive method for non-alcoholic fatty liver disease by food materials (2019)
  • Author(s): Inoue H, Watanabe H, Inaba Y
  • Organizer: The 7th International Conference on Food Factors
  • Int'l Joint Research / Invited
• [Presentation] Role of GKRP in impeded hepatic glucose uptake in type 2 diabetes (2019)
  • Author(s): Inoue H
  • Organizer: ATLAS symposium 2019 Tissue Plasticity of Obesity
  • Int'l Joint Research / Invited
• [Presentation] 視床下部による肝糖産生の調節とその異常 (2019)
  • Author(s): 井上啓
  • Organizer: 第40回日本臨床薬理学会学術総会
  • Invited
• [Presentation] NAFLDにおける肝糖取り込み障害のメカニズムと役割 (2019)
  • Author(s): 井上啓、渡邉一史、稲葉有香
  • Organizer: 第６回 肝臓と糖尿病・代謝研究会・第６２回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] Central insulin action and hepatic glucose metabolism (2019)
  • Author(s): Inoue H
  • Organizer: 9th Federation of the Asian and Oceanian Pysiological Societies (FAOPS) Congress
  • Int'l Joint Research
• [Presentation] 脳肝連関による糖代謝恒常性維持とその破綻 (2018)
  • Author(s): 井上啓
  • Organizer: 第39回日本肥満学会
  • Invited
• [Presentation] Vagal regulation of hepatic glucose metabolism and its disorder (2018)
  • Author(s): Inoue H
  • Organizer: 41st Annual Meeting of the Molecular Biology Society of Japan
  • Invited
• [Remarks] 金沢大学新学術創成研究機構栄養・代謝研究ユニット
  • URL: https://inoue.w3.kanazawa-u.ac.jp/index.html
• [Remarks] 金沢大学新学術創成研究機構革新的統合バイオ研究コア栄養・代謝研究ユニット
  • URL: https://inoue.w3.kanazawa-u.ac.jp
• [Remarks] 金沢大学新学術創成研究機構革新的統合バイオ研究コア栄養・代謝研究ユニット
  • URL: http://inoue.w3.kanazawa-u.ac.jp/index.html