Investigation of exercise resistance induced by hepatokine selenoprotein P

• Project/Area Number: 25461334
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kanazawa University
• Principal Investigator: Misu Hirofumi 金沢大学, 医学系, 准教授 (80447680)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ヘパトカイン / 運動抵抗性 / セレノプロテインP / 運動療法 / インスリン抵抗性 / 活性酸素 / 運動療法抵抗性

Outline of Final Research Achievements

We have previously identified selenoprotein P (SeP) as a type 2 diabetes-upregulated hepatokine that induces insulin resistance and hyperglycemia. In this study, we propose a novel pathological concept SeP-induced exercise resistance. We have found out that SeP impairs ROS-induced AMPK phosphorylation in cultured myotubes. SeP knockout mice showed increased sensitivity to exercise training. siRNA screening revealed that LRP1 functions as a SeP receptor in cultured myotubes. This study demonstrates that overproduction of SeP induces exercise resistance by suppressing ROS/AMPK through muscle receptor LRP1. Our study opens the door for inhibitors of SeP/LRP1 axis as new drugs for physical inactivity-associated diseases such as type 2 diabetes.

Research Products

• [Journal Article] Development of a Sol Particle Homogeneous Immunoassay for Measuring Full-Length Selenoprotein P in Human Serum. (2016)
  • Author(s): M. Tanaka, Y. Saito, H. Misu, S. Kato, Y. Kita, Y. Takeshita, T. Kanamori, T. Nagano, M. Nakagen, T. Urabe, T. Takamura, S. Kaneko, K. Takahashi and N. Matsuyama.
  • Journal Title: J Clin Lab Anal Volume: 30 Issue: 2 Pages: 114-122
  • DOI: 10.1002/jcla.21824
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Vildagliptin vs liraglutide as a second-line therapy switched from sitagliptin-based regimens in patients with type 2 diabetes: A randomized, parallel-group study. (2015)
  • Author(s): Takeshita Y, Takamura T, Kita Y, Otoda T, Kato K, Wakakuri H, Yamada M, Misu H, Matsushima Y, Kaneko S
  • Journal Title: J Diabetes Investig Volume: 6 Issue: 2 Pages: 192-200
  • DOI: 10.1111/jdi.12269
  • NAID: 120005774894
  • Peer Reviewed / Open Access
• [Journal Article] Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in Japanese patients with non-alcoholic fatty liver disease. (2015)
  • Author(s): Kato K, Takeshita Y, Misu H, Zen Y, Kaneko S, Takamura T.
  • Journal Title: J Diabetes Investig. Volume: 6 Issue: 2 Pages: 158-163
  • DOI: 10.1111/jdi.12271
  • NAID: 120005593987
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics of hepatic fatty acid compositions in patients with nonalcoholic steatohepatitis. (2015)
  • Author(s): Yamada K, Mizukoshi E, Sunagozaka H, Arai K, Yamashita T, Takeshita Y, Misu H, Takamura T, Kitamura S, Zen Y, Nakanuma Y, Honda M, Kaneko S.
  • Journal Title: Liver Int. Volume: 35(2) Issue: 2 Pages: 582-90
  • DOI: 10.1111/liv.12685
  • Peer Reviewed / Open Access
• [Journal Article] Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells. (2014)
  • Author(s): Ishikura K, Misu H, Kumazaki M, Takayama H, Matsuzawa-Nagata N, Tajima N, Chikamoto K, Lan F, Ando H, Ota T, Sakurai M, Takeshita Y, Kato K, Fujimura A, Miyamoto K, Saito Y, Kameo S, Okamoto Y, Takuwa Y, Takahashi K, Kidoya H, Takakura N, Kaneko S, Takamura T
  • Journal Title: Diabetologia Volume: 57 Issue: 9 Pages: 1968-1976
  • DOI: 10.1007/s00125-014-3306-9
  • NAID: 120005463349
  • Peer Reviewed / Open Access
• [Journal Article] The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism : a randomised controlled trial (2014)
  • Author(s): Y Takeshita, T Takamura, M Honda, Y Kita, Y Zen, KI Kato, H Misu, T Ota, M Nakamura, K Yamada, H Sunagozaka, K Arai, T Yamashita, E Mizukoshi, S Kaneko
  • Journal Title: Diabetologia Volume: 57(5) Issue: 5 Pages: 878-90
  • DOI: 10.1007/s00125-013-3149-9
  • Peer Reviewed / Open Access
• [Journal Article] Metformin Suppresses Expression of the Selenoprotein P gene via an AMPK-FoxO3a Pathway in H4IIEC3 Hepatocytes (2014)
  • Author(s): H Takayama, H Misu, H Iwama, K Chikamoto, Y Saito, K Murao, A Teraguchi, F Lan, A Kikuchi, R Saito, N Tajima, T Shirasaki, S Matsugo, KI Miyamoto, S Kaneko, T Takamura
  • Journal Title: J Biol Chem Volume: 289(1) Issue: 1 Pages: 335-45
  • DOI: 10.1074/jbc.m113.479386
  • Peer Reviewed
• [Journal Article] LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance (2014)
  • Author(s): Fei Lan, H Misu, K Chikamoto, H Takayam, A Kikuchi, K Mohri, N Takata, H Hayashi, N Matsuzawa-Nagata, Y Takeshita, H Noda, Y Matsumoto, T Ota, T Nagano, M Nakagen, K Miyamoto, K Takatsuki, T Seo, K Iwayama, K Tokuyama, S Matsugo, H Tang, Y Saito, S Yamagoe, S Kaneko, T Takamura
  • Journal Title: Diabete Volume: 63 Issue: 5 Pages: 1649-1664
  • DOI: 10.2337/db13-0728
  • Peer Reviewed / Open Access
• [Journal Article] Ectopic fat accumulation and distant organ-specific insulin resistance in Japanese people with nonalcoholic Fatty liver disease (2014)
  • Author(s): K Kato, T Takamura, Y Takeshita, Y Ryu, H Misu, T Ota, K Tokuyama, S Nagasaka, M Matsuhisa, O Matsui, S Kaneko
  • Journal Title: PLoS One Volume: 9(3) Issue: 3 Pages: e92170-e92170
  • DOI: 10.1371/journal.pone.0092170
  • NAID: 120005440398
  • Peer Reviewed / Open Access
• [Presentation] ヘパトカインセレノプロテインPは骨格筋受容体LRP1を介して運動療法抵抗性を惹起する (2016)
  • Author(s): 高山浩昭, 御簾博文, 菊地晶裕, 石井清朗, 斎藤芳郎, 金子周一, 篁俊成
  • Organizer: 第30回日本糖尿病肥満動物学会
  • Place of Presentation: 大宮ソニックシティ(埼玉)
  • Year and Date: 2016-03-11
• [Presentation] ヘパトカインセレノプロテインPは筋受容体LRP1を介して“運動療法抵抗性”を惹起する (2015)
  • Author(s): 高山浩昭, 御簾博文, 斎藤芳郎, 金子周一, 篁俊成
  • Organizer: 第27回分子糖尿病シンポジウム
  • Place of Presentation: 丸ビルホール＆コンファレンススクエア(東京)
  • Year and Date: 2015-12-05
• [Presentation] ヘパトカインSePと筋受容体LRP1よる運動感受性制御 (2015)
  • Author(s): 御簾博文, 高山浩昭, 金子周一, 篁. 俊成
  • Organizer: 第30回日本糖尿病合併症学会
  • Place of Presentation: 愛知県産業労働センターウインクあいち
  • Year and Date: 2015-11-27
• [Presentation] Hepatokine selenoprotein P induces exercise resistance via skeletal muscle receptor LRP1. (2015)
  • Author(s): Hirofumi Misu, Toshinari Takamura and Shuichi Kaneko
  • Organizer: Japan Digestive Disease Week 2015 International Session (Workshop)
  • Place of Presentation: Grand Prince Hotel New Takanawa (Tokyo)
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] Hepatokine selenoprotein P and skeletal muscle receptor LRP1 induce exercise resistance by inhibition of ROS and AMPK. (2015)
  • Author(s): Hirofumi Misu
  • Organizer: The 46th NIPS (National Institute of Physiological Science) International Symposium
  • Place of Presentation: Nagoya Congress Center
  • Year and Date: 2015-10-02
  • Int'l Joint Research / Invited
• [Presentation] ヘパトカインセレノプロテインP血中濃度による運動療法抵抗性の予知に関する検討 (2015)
  • Author(s): 御簾博文, 田中睦, 斎藤芳郎, 石井清朗, 竹下有美枝, 金森岳広, 赤澤暢彦, 前田清司, 竹越一博, 金子周一, 篁 俊成
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京第一ホテル下関 (山口)
  • Year and Date: 2015-05-23
• [Presentation] ヘパトカインselenoprotein P・LECT2による インスリン感受性の制御機構 (2015)
  • Author(s): 御簾博文
  • Organizer: 第29回日本糖尿病肥満動物学会
  • Place of Presentation: 京都大学
  • Year and Date: 2015-02-14
  • Invited
• [Presentation] 糖尿病関連ヘパトカインセレノプロテインPはVEGF抵抗性を介して血管新生を障害する (2014)
  • Author(s): 御簾博文、石倉和秀、高山浩昭、金子周一、篁 俊成
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-11-27
• [Presentation] ヘパトカインセレノプロテインPは AMPK不活化を介して 運動療法の抵抗性を惹起する (2014)
  • Author(s): 御簾博文
  • Organizer: 第35回日本肥満学会
  • Place of Presentation: 宮崎シーガイア
  • Year and Date: 2014-10-25
  • Invited
• [Presentation] 2型糖尿病の病態形成における ヘパトカインセレノプロテインPの役割 (2014)
  • Author(s): 御簾博文
  • Organizer: 第29回日本糖尿病合併症学会
  • Place of Presentation: 東京都市センターホテル
  • Year and Date: 2014-10-03
  • Invited
• [Presentation] 抗酸化ヘパトカインセレノプロテインPはVEGF抵抗性を介して糖尿病性血管新生障害に寄与する (2014)
  • Author(s): 御簾博文、石倉和秀、斎藤芳郎、金子周一、篁 俊成
  • Organizer: 第65回日本酸化ストレス学会学術集会
  • Place of Presentation: 同志社大学(京都)
  • Year and Date: 2014-09-05
• [Presentation] 飽食感知へパトカインLECT2の同定と その機能解析 (2014)
  • Author(s): 御簾博文、篁 俊成、金子周一
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ(東京)
  • Year and Date: 2014-05-29
• [Presentation] インスリン抵抗性誘導ヘパトカイン セレノプロテインPの 骨格筋における受容体の探索 (2014)
  • Author(s): 御簾博文、高山浩昭、蘭 菲、 田島奈津美、菊地晶裕、石井清朗、 金子周一、篁 俊成
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: リーガロイヤルホテル大阪
  • Year and Date: 2014-05-24
• [Presentation] 肥満関連へパトカイン LECT2の同定 (2014)
  • Author(s): 御簾博文、Lan Fei、近本啓太、松郷誠一、高山浩昭、山越智、金子周一、篁 俊成
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2014-04-24
• [Presentation] A novel role for selenoprotein P in the regulation of insulin sensitivity (2014)
  • Author(s): Hirofumi Misu, Yohiro Saito, Kazuhiko Takahashi, Toshinari Takamura, Shuichi Kaneko.
  • Organizer: 17th Biennial Meeting of Society for Free Radical Research International (SFRRI 2014)
  • Place of Presentation: Kyoto International Conference Center
  • Invited
• [Presentation] Circulating levels of selenoprotein P predict future hyperglycemia in nondiabetic Japanese people
  • Author(s): Hirofumi Misu, Takehiro Kanamori, YumieTakeshita, Yohiro Saito, Mutsumi Tanaka, Shuichi Kaneko, Toshinari Takamura.
  • Organizer: 49th Annual Meeting of the European Association for the Study of Diabetes (EASD2013)
  • Place of Presentation: Fila de Barcelona's Gran Via exhibition centre, Spain
• [Presentation] ヘパトカインセレノプロテインPは活性酸素/AMPK/PGC1α経路の抑制を介して”運動療法抵抗性”を誘導する
  • Author(s): 御簾博文, 蘭 菲, 近本啓太, 高山浩昭, 菊地昌裕, 斎藤芳郎, 金子周一, 篁俊成.
  • Organizer: 第36回日本分子生物学会年次学術集会
  • Place of Presentation: 神戸国際会議場
• [Presentation] インスリン抵抗性誘導へパトカインセレノプロテインPによる高血糖発症予知に関する検討
  • Author(s): 御簾博文, 田中睦, 斎藤芳郎, 竹下有美枝, 喜多裕樹, 中源雅俊, 長野亨, 金子周一, 篁 俊成.
  • Organizer: 第56回日本糖尿病年次学術集会
  • Place of Presentation: 熊本市民会館
• [Presentation] ヘパトカインセレノプロテインPによる運動療法抵抗性発症に関する検討
  • Author(s): 御簾博文, Lan Fei, 高山浩昭, 金子周一, 篁 俊成.
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台国際会議場