Development of exercise-enhancing therapy targeting the liver-skeletal muscle network

• Project/Area Number: 18K19560
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: Kanazawa University
• Principal Investigator: Takamura Toshinari 金沢大学, 医学系, 教授 (00324111)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 糖尿病 / 肥満症 / サルコペニア / 薬剤スクリーニング / 運動効果 / 健康寿命 / セレノプロテインP / ヘパトカイン / 2型糖尿病 / 分泌タンパク質 / 化合物スクリーニング / 遺伝子発現 / インスリン抵抗性 / 運動療法 / 肝臓 / 骨格筋

Outline of Final Research Achievements

Since we found that selenoprotein P (SeP) secreted by the liver induces resistance to exercise, we conducted a screening to identify small-molecule compounds that specifically suppress SeP expression in the liver and enhance the exercise effect. As a result, we identified about 50 small-molecule compounds that potently suppress the transcriptional activity of SeP. Among these, we selected three compounds with low toxicity. We administered these compounds to liver cell lines and mice and confirmed the inhibitory effect on SeP expression.

Academic Significance and Societal Importance of the Research Achievements

高齢化を背景に糖尿病、肥満症、サルコペニアが増大しており、運動効果を高める治療が求められている。今回同定したSeP発現抑制薬はこれまでにない運動効果増強薬となるだけでなく、2型糖尿病、脂肪肝、脂質異常症といった運動療法が効果を発揮するとされる多くの疾患に対しても全く新しい治療法になる可能性がある。さらに運動療法が持つ寿命延長効果をも増強することが出来れば、健康寿命延長薬の開発につながることが期待される。

Research Products

• [Journal Article] LECT2 as a hepatokine links liver steatosis to inflammation via activating tissue macrophages in NASH (2021)
  • Author(s): Takata Noboru、Ishii Kiyo-aki、Takayama Hiroaki、Nagashimada Mayumi、Kamoshita Kyoko、Tanaka Takeo、Kikuchi Akihiro、Takeshita Yumie、Matsumoto Yukako、Ota Tsuguhito、Yamamoto Yasuhiko、Yamagoe Satoshi、Seki Akihiro、Sakai Yoshio、Kaneko Shuichi、Takamura Toshinari
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 555-555
  • DOI: 10.1038/s41598-020-80689-0
  • Peer Reviewed / Open Access
• [Journal Article] Alcohol Intake Is Associated With Elevated Serum Levels of Selenium and Selenoprotein P in Humans (2021)
  • Author(s): Isobe Yuki、Asakura Hiroki、Tsujiguchi Hiromasa、Kannon Takayuki、Takayama Hiroaki、Takeshita Yumie、Ishii Kiyo-aki、Kanamori Takehiro、Hara Akinori、Yamashita Tatsuya、Tajima Atsushi、Kaneko Shuichi、Nakamura Hiroyuki、Takamura Toshinari
  • Journal Title: Frontiers in Nutrition Volume: 8 Pages: 633703-633703
  • DOI: 10.3389/fnut.2021.633703
  • Peer Reviewed / Open Access
• [Journal Article] Acute Hyperenergetic, High-Fat Feeding Increases Circulating FGF21, LECT2, and Fetuin-A in Healthy Men (2020)
  • Author(s): Willis Scott A、Sargeant Jack A、Yates Thomas、Takamura Toshinari、Takayama Hiroaki、Gupta Vinay、Brittain Emily、Crawford Joe、Parry Si?n A、Thackray Alice E、Varela-Mato Veronica、Stensel David J、Woods Rachel M、Hulston Carl J、Aithal Guruprasad P、King James A
  • Journal Title: The Journal of Nutrition Volume: 150 Issue: 5 Pages: 1076-1085
  • DOI: 10.1093/jn/nxz333
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hepatokine Selenoprotein P-Mediated Reductive Stress Causes Resistance to Intracellular Signal Transduction (2020)
  • Author(s): Takamura Toshinari
  • Journal Title: Antioxidants & Redox Signaling Volume: 33 Issue: 7 Pages: 517-524
  • DOI: 10.1089/ars.2020.8087
  • Peer Reviewed / Open Access
• [Journal Article] Secondary analyses to assess the profound effects of empagliflozin on endothelial function in patients with type?2 diabetes and established cardiovascular diseases: The placebo‐controlled double‐blind randomized effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi‐center placebo‐controlled double‐blind randomized trial (2020)
  • Author(s): Tanaka Atsushi、Shimabukuro Michio、Machii Noritaka、Teragawa Hiroki、Okada Yosuke、Shima Kosuke R.、Takamura Toshinari、Taguchi Isao、Hisauchi Itaru、Toyoda Shigeru、Matsuzawa Yasushi、Tomiyama Hirofumi、Yamaoka‐Tojo Minako、Ueda Shinichiro、Higashi Yukihito、Node Koichi
  • Journal Title: Journal of Diabetes Investigation Volume: 11 Issue: 6 Pages: 1551-1563
  • DOI: 10.1111/jdi.13289
  • Peer Reviewed / Open Access
• [Journal Article] Plasma half-life and tissue distribution of leukocyte cell-derived chemotaxin 2 in mice (2020)
  • Author(s): Kikuchi Akihiro、Takayama Hiroaki、Tsugane Hirohiko、Shiba Kazuhiro、Chikamoto Keita、Yamamoto Tatsuya、Matsugo Seiichi、Ishii Kiyo-aki、Misu Hirofumi、Takamura Toshinari
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 13260-13260
  • DOI: 10.1038/s41598-020-70192-x
  • NAID: 120007185663
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between handgrip strength and albuminuria in community-dwelling elderly Japanese subjects: the Shika Study (2020)
  • Author(s): Hara Akinori、Tsujiguchi Hiromasa、Suzuki Keita、Tao Yuichi、Nakamura Haruki、Kasahara Tomoko、Nguyen Thao Thi Thu、Miyagi Sakae、Shimizu Yukari、Kannon Takayuki、Tajima Atsushi、Wada Takashi、Takamura Toshinari、Nakamura Hiroyuki
  • Journal Title: Biomarkers Volume: 25 Issue: 7 Pages: 587-593
  • DOI: 10.1080/1354750x.2020.1819418
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metabolic and sympathovagal effects of bolus insulin glulisine versus basal insulin glargine therapy in people with type?2 diabetes: A randomized controlled study (2020)
  • Author(s): Takeshita Yumie、Tanaka Takeo、Wakakuri Hitomi、Kita Yuki、Kanamori Takehiro、Takamura Toshinari
  • Journal Title: Journal of Diabetes Investigation Volume: in press Issue: 7 Pages: 1193-1201
  • DOI: 10.1111/jdi.13471
  • Peer Reviewed / Open Access
• [Journal Article] Circulating Concentrations of Insulin Resistance-Associated Hepatokines, Selenoprotein P and Leukocyte Cell-Derived Chemotaxin 2, during an Oral Glucose Tolerance Test in Humans (2019)
  • Author(s): Mohri K, Misu H, Takayama H, Ishii KA, Kikuchi A, Lan F, Enyama Y, Takeshita Y, Saito Y, Kaneko S,Takamura T.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 42 Issue: 3 Pages: 373-378
  • DOI: 10.1248/bpb.b18-00549
  • NAID: 130007607371
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2019-03-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induction of Selenoprotein P mRNA during Hepatitis C Virus Infection Inhibits RIG-I-Mediated Antiviral Immunity. (2019)
  • Author(s): Murai K, Honda M, Shirasaki T, Shimakami T, Omura H, Misu H, Kita Y, Takeshita Y, Ishii KA, Takamura T, Urabe T, Shimizu R, Okada H, Yamashita T, Sakai Y, Kaneko S.
  • Journal Title: Cell Host Microbe Volume: 10;25(4) Issue: 4 Pages: 588-601
  • DOI: 10.1016/j.chom.2019.02.015
  • Peer Reviewed / Open Access
• [Journal Article] p62-mediated autophagy affects nutrition-dependent insulin receptor substrate 1 dynamics in 3T3-L1 preadipocytes (2019)
  • Author(s): Igawa Hirobumi、Kikuchi Akihiro、Misu Hirofumi、Ishii Kiyo-aki、Kaneko Shuichi、Takamura Toshinari
  • Journal Title: Journal of Diabetes Investigation Volume: 10 Issue: 1 Pages: 32-42
  • DOI: 10.1111/jdi.12866
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of Human Selenoprotein P Determinants in Serum between Our Original Methods and Commercially Available Kits (2018)
  • Author(s): Saito Yoshiro、Misu Hirofumi、Takayama Hiroaki、Takashima Shin-ichiro、Usui Soichiro、Takamura Masayuki、Kaneko Shuichi、Takamura Toshinari、Noguchi Noriko
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 41 Issue: 5 Pages: 828-832
  • DOI: 10.1248/bpb.b18-00046
  • NAID: 130006730702
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2018-05-01
  • Peer Reviewed / Open Access
• [Journal Article] Endogenous Selenoprotein P, a Liver-Derived Secretory Protein, Mediates Myocardial Ischemia/Reperfusion Injury in Mice. (2018)
  • Author(s): Chikata A, Kato T, Usuda K, Fujita S, Maruyama M, Nagata Y, Sakagami S, Kanamori N, Yaegashi T, Saeki T, Kusayama T, Usui S, Furusho H, Kaneko S, Takamura M.
  • Journal Title: Int J Mol Sci. Volume: 19 Issue: 3 Pages: 878-878
  • DOI: 10.3390/ijms19030878
  • Peer Reviewed / Open Access
• [Journal Article] Serum selenoprotein P, but not selenium, predicts future hyperglycemia in a general Japanese population. (2018)
  • Author(s): Oo SM, Misu H, Saito Y, Tanaka M, Kato S, Kita Y, Takayama H, Takeshita Y, Kanamori T, Nagano T, Nakagen M, Urabe T, Matsuyama N, Kaneko S, Takamura T.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 16727-16727
  • DOI: 10.1038/s41598-018-35067-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The influence of adiposity and acute exercise on circulating hepatokines in normal-weight and overweight/obese men (2017)
  • Author(s): Sargeant Jack A.、Aithal Guruprasad P.、Takamura Toshinari、Misu Hirofumi、Takayama Hiroaki、Douglas Jessica A.、Turner Mark C.、Stensel David J.、Nimmo Myra A.、Webb David R.、Yates Thomas、King James A.
  • Journal Title: Appl Physiol Nutr Metab Volume: 3 Issue: 5 Pages: 1-9
  • DOI: 10.1139/apnm-2017-0639
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Novel role of selenoprotein P in immunity (2020)
  • Author(s): 篁俊成
  • Organizer: 第63回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] NAFLD/NASH研究の最前線～連続肝生検から見えてきたdiabetic steatohepatitis～ (2020)
  • Author(s): 篁俊成
  • Organizer: 第63回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] 摂取カロリー設定と3大栄養素バランスに関する論考 Issues on dietary calorie and macronutrient balance (2019)
  • Author(s): 篁 俊成
  • Organizer: 第92回日本内分泌学会学術総会
  • Invited
• [Presentation] Diabetes-associated systemic pathology induced by hepatokines (2019)
  • Author(s): 御簾 博文，篁 俊成
  • Organizer: 第63回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] 抗酸化ヘパトカイン”セレノプロテインP”が惹起する全身の糖尿病関連病態 (2019)
  • Author(s): 高山 浩昭、御簾 博文、斎藤 芳郎、篁 俊成
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] EPA製剤が2型糖尿病患者の血中セレノプロテインP濃度と臓器特異的インスリン感受性に及ぼす効果 (2019)
  • Author(s): 寺村 千里，竹下 有美枝，高山 浩昭 ，海古井 由佳，田中 健雄，金森 岳広，篁 俊成
  • Organizer: 第34回日本糖尿病合併症学会
• [Presentation] インスリン抵抗性や運動抵抗性を惹起するセレノプロテインPに対するEPAの制御機構 (2019)
  • Author(s): 鴨下 恭子，石井 清明，田島 奈津美，白崎 尚芳，高山 浩昭，竹下 有美枝，金子 周一，篁 俊成
  • Organizer: 第34回日本糖尿病合併症学会
• [Presentation] Search for inhabitors against selenoprotein P that cause insulin resistance and excersise resistance. (2019)
  • Author(s): Xingyu Yao, Hiroaki Takayama, Kiyo-aki Ishii, Toshinari Takamura
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Locally-circulating selenoprotein P regulates ROS-mediated thermogenesis in brown fat (2019)
  • Author(s): Hein Ko Oo、高山 浩昭、Swe Mar Oo、石井 清朗、篁 俊成
  • Organizer: 第31回分子糖尿病学シンポジウム
• [Presentation] Anti-oxidative hepatokine selenoprotein P impairs brown fat thermogenesis by suppressing mitochondrial ROS (2019)
  • Author(s): Hiroaki Takayama, Swe Mar Oo, Hirofumi Misu, Kiyo-aki Ishii, Toshinari Takamura
  • Organizer: Keystone Symposia Obesity and Adipose Tissue Biology
  • Int'l Joint Research
• [Presentation] 非アルコール性脂肪性肝疾患のReal-World Date：肝病理進展に寄与する病態 (2019)
  • Author(s): 篁 俊成
  • Organizer: 第53回糖尿病学の進歩
  • Invited
• [Presentation] Gamma-glutamyltransferase levels reflect glycaemic status in type 2 diabetic people treated with an SGLT2 inhibitor (2018)
  • Author(s): T. Takamura, K. Kaku, A. Yoshida, H. Kusakabe, H. Suganami
  • Organizer: the 54th EASD Annual Meeting 2018 in Berlin, Germany
  • Int'l Joint Research
• [Presentation] 肝臓-骨格筋連関が形成する糖尿病の新病態 (2018)
  • Author(s): 篁 俊成
  • Organizer: 第5回肝臓と糖尿病・代謝研究会
  • Invited
• [Presentation] Lessons from type 2 diabetic liver (2018)
  • Author(s): 篁 俊成
  • Organizer: 第84回日本生化学会東北支部会
  • Invited
• [Book] 「ビタミン欠乏症・過剰症・依存症」 (2021)
  • Author(s): 篁俊成
  • Total Pages: 3
  • Publisher: 医学書院
• [Book] Non-Alcoholic Fatty Liver Diseases (2019)
  • Author(s): Shuichi Kaneko, Toshinari Takamura, Hirofumi Misu
  • Total Pages: 202
  • Publisher: Wiley
  • ISBN: 9784939028687
• [Remarks] 金沢大学大学院 医学系研究科 内分泌・代謝内科学
  • URL: https://metabology.w3.kanazawa-u.ac.jp/
• [Remarks] 金沢大学 内分泌・代謝内科学分野
  • URL: https://www.facebook.com/TakamuraLab/