The role of Nrf2 in oxidative stress-mediated insulin resistance

• Project/Area Number: 26460383
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Akira Uruno 東北大学, 医学系研究科, 講師 (90396474)
• Co-Investigator(Renkei-kenkyūsha): YAMAMOTO MASAYUKI 東北大学, 大学院医学系研究科, 教授 (50166823)
• Research Collaborator: YAGISHITA YOKO 東北大学, 大学院医学系研究科, 研究員 (50733838)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 糖尿病 / 肥満 / 酸化ストレス / Nrf2 / セレノシステイン / 代謝学 / インスリン抵抗性 / レプチン抵抗性 / Keap1 / 視床下部 / 膵β細胞

Outline of Final Research Achievements

The numbers of type 2 diabetes mellitus patients are increasing due to the change of life pattern. As it is important to clarify the parthenogenesis of diabetes mellitus, we tried to clarify it.
We generated conditional knockout mice of selenocysteine transfer RNA (Trsp) gene by using rat insulin promoter Cre (TrspRIPKO). The TrspRIP KO mice displayed increments of oxidative stress in hypothalamus.We also found that the mice displayed insulin and leptin resistance to develop obesity and diabetes mellitus. Obesity and diabetes mellitus due to oxidative stress were diminished by activation of Nrf2 signaling in hypothalamus.These results indicate that Nrf2 is a promising target for treatment and prevention of obesity and diabetes mellitus.

Research Products

• [Journal Article] The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. (2017)
  • Author(s): Higashi C, Kawaji A, Tsuda N, Hayashi M, Saito R, Yagishita Y, Suzuki T, Uruno A, Nakamura M, Nakao K, Furusako S, Yamamoto M.
  • Journal Title: Eur J Pharmacol Volume: 802 Pages: 76-84
  • DOI: 10.1016/j.ejphar.2017.02.044
  • Peer Reviewed / Open Access
• [Journal Article] Nrf2 Improves Leptin and Insulin Resistance Provoked by Hypothalamic Oxidative Stress. (2017)
  • Author(s): Yagishita Y, Uruno A, Fukutomi T, Saito R, Saigusa D, Pi J, Fukamizu A, Sugiyama F, Takahashi S, Yamamoto M.
  • Journal Title: Cell Rep Volume: 18 Issue: 8 Pages: 2030-2044
  • DOI: 10.1016/j.celrep.2017.01.064
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism. (2016)
  • Author(s): Uruno A, Yagishita Y, Katsuoka F, Kitajima Y, Nunomiya A, Nagatomi R, Pi J, Biswal SS, Yamamoto M.
  • Journal Title: Mol Cell Biol Volume: 36 Issue: 11 Pages: 1655-1672
  • DOI: 10.1128/mcb.01095-15
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Nrf2-mediated regulation of skeletal muscle glycogen metabolism. (2016)
  • Author(s): Uruno A, Yagishita Y, Katsuoka F, Kitajima Y, Nunomiya A, Nagatomi R, Pi J, Biswal SS, Yamamoto M.
  • Journal Title: Mol Cell Biol. Volume: 36
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of RXR agonists on cell proliferation/apoptosis and ACTH secretion/Pomc expression (2015)
  • Author(s): Saito-Hakoda A, Uruno A, Yokoyama A, Shimizu K, Parvin R, Kudo M, Saito-Ito T, Sato I, Kogure N, Suzuki D, Shimada H, Yoshikawa T, Fujiwara I, Kagechika H, Iwasaki Y, Kure S, Ito S, Sugawara A
  • Journal Title: PLoS One Volume: 10 Issue: 12 Pages: e0141960-e0141960
  • DOI: 10.1371/journal.pone.0141960
  • Peer Reviewed / Open Access
• [Journal Article] The Keap1-Nrf2 system and diabetes mellitus. (2015)
  • Author(s): Uruno A, Yagishita Y, Yamamoto M.
  • Journal Title: Arch Biochem Biophys. Volume: 566 Pages: 76-84
  • DOI: 10.1016/j.abb.2014.12.012
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Angiotensin II receptor blockers differentially affect CYP11B2 expression in human adrenal H295R cells. (2014)
  • Author(s): Matsuda K, Uruno A, Kogure N, Sugawara K, Shimada H, Nezu M, Saito-Ito T, Iki Y, Kudo M, Shimizu K, Sato I, Yoshikawa T, Satoh F, Ito R, Yokoyama A, Rainey WE, Saito-Hakoda A, Ito S, Sugawara A.
  • Journal Title: Mol Cell Endocrinol. Volume: 383(1-2) Issue: 1-2 Pages: 60-68
  • DOI: 10.1016/j.mce.2013.12.004
  • Peer Reviewed
• [Journal Article] Isocitrate dehydrogenase mutation is frequently observed in giant cell tumor of bone (2014)
  • Author(s): Kato-Kaneko M, Liu X, Oki H, Ogasawara S, Nakamura T, Saidoh N, Tsujimoto Y, Matsuyama Y, Uruno A, Sugawara M, Tsuchiya T, Yamakawa M, Yamamoto M, Takagi M, Kato Y.
  • Journal Title: Cancer Sci Volume: 105 Issue: 6 Pages: 744-748
  • DOI: 10.1111/cas.12413
  • Peer Reviewed / Open Access
• [Journal Article] Transcription factor NF-E2-related factor 1 impairs glucose metabolism in mice. (2014)
  • Author(s): Hirotsu Y, Higashi C, Fukutomi T, Katsuoka F, Tsujita T, Yagishita Y, Matsuyama Y, Motohashi H, Uruno A, and Yamamoto M.
  • Journal Title: Mol Cell Biol Volume: 19 Issue: 8 Pages: 650-665
  • DOI: 10.1111/gtc.12165
  • Peer Reviewed / Open Access
• [Journal Article] Transcription factor Nrf1 negatively regulates the cystine/glutamate transporter and lipid-metabolizing enzymes (2014)
  • Author(s): Tsujita T, Peirce V, Baird L, Matsuyama Y, Takaku M, Walsh SV, Griffin JL, Uruno A, Yamamoto M, and Hayes JD.
  • Journal Title: Mol Cell Biol Volume: 34 Issue: 20 Pages: 3800-3816
  • DOI: 10.1128/mcb.00110-14
  • Peer Reviewed / Open Access
• [Journal Article] Retinoic acid receptor-α up-regulates proopiomelanocortin gene expression in AtT20 corticotroph cells (2014)
  • Author(s): Uruno, A.; Saito-Hakoda, A.; Yokoyama, A.; Kogure, N.; Matsuda, K.; Parvin, R.; Shimizu, K.; Sato, I.; Kudo, M.; Yoshikawa, T.; Kagechika, H.; Iwasaki, Y.; Ito, S.; Sugawara, A.
  • Journal Title: Endocrine Journal Volume: 61 Issue: 11 Pages: 1105-1114
  • DOI: 10.1507/endocrj.EJ14-0115
  • NAID: 130004677954
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed
• [Journal Article] Nrf2 induces fibroblast growth factor 21 in diabetic mice (2014)
  • Author(s): Furusawa Y, Uruno A, Yagishita Y, Higashi C, and Yamamoto M.
  • Journal Title: Genes Cells Volume: 19 Issue: 12 Pages: 864-878
  • DOI: 10.1111/gtc.12186
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 糖尿病におけるKeap1-Nrf2系の役割 (2016)
  • Author(s): 宇留野晃、柳下陽子、山本雅之
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台（仙台国際センター）
  • Year and Date: 2016-09-25
  • Invited
• [Presentation] Nrf2によるグリコーゲン分枝鎖酵素遺伝子発現制御機構の解明 (2016)
  • Author(s): 相川享、宇留野晃、柳下陽子、山本雅之
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台（仙台国際センター）
  • Year and Date: 2016-09-25
• [Presentation] A novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. (2016)
  • Author(s): Higashi C, Hayashi M, Tsuda N, Kawaji A, Nakao K, Satoh F, Nakamura M, Furusako S, Saito R, Suzuki T, Uruno A, Yamamoto M.
  • Organizer: The 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis
  • Place of Presentation: ロンドン（イギリス）
  • Year and Date: 2016-09-14
  • Int'l Joint Research
• [Presentation] Identification and Evaluation of Isothiazole-Based Novel Nrf2 inducers (2016)
  • Author(s): Saitoh F, Kamino T, Nakahara M, Mizuno T, Takeuchi K, Arai Y, Chiyoda K, Kawamoto M, Maeda Y, Higashi C, Hayashi M, Tsuda N, Kawaji A, Murai T, Uchida K, Kamiya M, Naba H, Nakao K, Furusako S, Uruno A, Yamamoto M.
  • Organizer: The 35th National Medicinal Chemistry Symposium
  • Place of Presentation: シカゴ（アメリカ合衆国）
  • Year and Date: 2016-06-26
  • Int'l Joint Research
• [Presentation] イソチアゾール骨格を有する新規Nrf2活性化剤の創製 (2016)
  • Author(s): 斉藤文彦、神野智之、中原基、水野貴志、竹内勝俊、荒井ゆかり、千代田幸治、川本雅毅、前田能崇、東知佳、林真貴子、津田直人、河路淳子、村井武彦、内田一也、神谷昌嗣、那波弘康、中尾一成、古迫正司、宇留野晃、山本雅之
  • Organizer: 第34回メディシナルケミストリーシンポジウム
  • Place of Presentation: つくば（つくば国際会議場）
• [Presentation] 骨格筋におけるNrf2のグリコーゲン代謝制御機構 (2015)
  • Author(s): 宇留野晃、柳下陽子、山本雅之
  • Organizer: 第88回日本生化学会大会合同大会(BMB2015)
  • Place of Presentation: 神戸 (神戸ポートアイランド)
  • Year and Date: 2015-12-03
• [Presentation] Keap1-Nrf2システムによるTrsp欠失マウス膵β細胞および視床下部の酸化ストレス防御機構 (2015)
  • Author(s): 柳下陽子、福富俊明、宇留野晃、山本雅之
  • Organizer: 第38回分子生物学会/第88回日本生化学会大会合同大会(BMB2015)
  • Place of Presentation: 神戸 (神戸ポートアイランド)
  • Year and Date: 2015-12-03
• [Presentation] Nrf2 regulates glucose metabolism-related genes (2015)
  • Author(s): Yagishita Y, Uruno A, Katsuoka F, Funayama R, Nakayama K, Kensler TW, Yamamoto M.
  • Organizer: 27th Annyal UPCI Scientific Retreat
  • Place of Presentation: Pittsburgh (アメリカ合衆国)
  • Year and Date: 2015-06-18
  • Int'l Joint Research
• [Presentation] レチノイドX受容体アゴニストPA024が副腎CYP11B2発現・アルドステロン分泌に及ぼす影響の検討 (2015)
  • Author(s): 鈴木大、箱田明子、清水恭子、パービンレハナ、宇留野晃、青木聡、佐藤郁子、島田洋樹、小暮直敬、藤原幾磨、伊藤貞嘉、影近弘之、横山敦、菅原明
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 東京 (ホテルニューオータニ)
  • Year and Date: 2015-04-23
• [Presentation] 種々のレチノイドX受容体アゴニストは, AtT20細胞の増殖・アポトーシス・Pomc発現・ACTH分泌に異なる影響を及ぼす (2015)
  • Author(s): 箱田明子、宇留野晃、清水恭子、パービンレハナ、横山敦、吉川雄朗、工藤正孝、影近弘之、岩崎泰正、伊藤貞嘉、菅原明
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 東京 (ホテルニューオータニ)
  • Year and Date: 2015-04-23
• [Presentation] Pomc遺伝子のグルココルチコイドによるネガティブ・レギュレーションにおけるNeuroD1の関与 (2015)
  • Author(s): パービンレハナ、箱田明子、清水恭子、宇留野晃、鈴木大、青木聡、島田洋樹、小暮直敬、工藤正孝、岩崎泰正、伊藤貞嘉、横山敦、菅原明
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 東京 (ホテルニューオータニ)
  • Year and Date: 2015-04-23
• [Presentation] Nrf2 regulates glycogen metabolism in skeletal muscle. (2015)
  • Author(s): Uruno A, Yagishita Y, Yamamoto M.
  • Organizer: The Keap1/Nrf2 Pathway in Health and Disease
  • Place of Presentation: Cambridge (Robinson College)
  • Year and Date: 2015-01-07
• [Presentation] Nrf2 regulates glucose metabolism-related genes. (2015)
  • Author(s): Yagishita Y, Uruno A, Katsuoka F, Funayama R, Nakayama K, Yamamoto M.
  • Organizer: The Keap1/Nrf2 Pathway in Health and Disease
  • Place of Presentation: Cambridge (Robinson College)
  • Year and Date: 2015-01-07
• [Presentation] Nrf2による酸化ストレス糖尿病モデルマウスの膵β細胞保護 (2014)
  • Author(s): 柳下陽子、宇留野晃、福富俊明、菅原明、山本雅之
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都（国立京都国際会館）
  • Year and Date: 2014-10-17
• [Presentation] Nrf2による糖尿病の発症抑制作用 (2014)
  • Author(s): 宇留野晃、古澤祐樹、柳下陽子、山本雅之
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都（国立京都国際会館）
  • Year and Date: 2014-10-17
• [Presentation] Keap1-Nrf2システムは糖尿病発症を抑制する (2014)
  • Author(s): 宇留野晃、古澤祐樹、柳下陽子、福富俊明、山本雅之
  • Organizer: 第80回日本生化学会東北支部例会
  • Place of Presentation: 秋田（アキタパークホテル）
  • Year and Date: 2014-05-10
• [Book] Molecular Nutrition and Diabetes, 1st Edition. (2015)
  • Author(s): Yagishita Y, Uruno A, Yamamoto M
  • Total Pages: 400
  • Publisher: Elsevier Science B.V.
• [Remarks] 酸化ストレスが糖尿病を引き起こすメカニズムを解明
  • URL: http://www.med.tohoku.ac.jp/news/3391.html
• [Remarks]
  • URL: http://www.dmbc.med.tohoku.ac.jp/official/index.html