roles of intracellular proteolytic systems in maintaining energy metabolism homeostasis

• Project/Area Number: 26461329
• 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: Takamura Toshinari 金沢大学, 医学系, 教授 (00324111)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: エネルギー代謝 / インスリン抵抗性 / 糖尿病 / 肥満症 / 脂肪肝 / プロテアソーム / タンパク質分解 / オートファジー / インスリン作用 / タンパク質代謝 / 肥満

Outline of Final Research Achievements

To understand the roles of intracellular proteolytic systems in maintaining energy metabolism homeostasis, the present study addressed the following three unresolved issues. ①Mechanisms underlying proteasome dysfunction in obesity, ②Significance of compensatory autophagy and its substrates under inhibition of proteasome activity and starvation, ③Significance of proteasome dysfunction in skeletal muscle in insulin sensitivity

Research Products

• [Journal Article] Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle. (2017)
  • Author(s): H Misu, H Takayama, Y Saito, Y Mita, A Kikuchi, K Ishii, K Chikamoto, T Kanamori, N Tajima, F Lan, Y Takeshita, M Honda, M Tanaka, S Kato, N Matsuyama, Y Yoshioka, Iwayama K, Tokuyama K, Akazawa N, Maeda S, Takekoshi K, Matsugo S, Noguchi N, S Kaneko, T Takamura.
  • Journal Title: Nature Med Volume: 23 Issue: 4 Pages: 508-516
  • DOI: 10.1038/nm.4295
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Where does liver fat go? A possible molecular link between fatty liver and diabetes (2017)
  • Author(s): Akihiro Kikuchi, Toshinari Takamura
  • Journal Title: J. Diabetes Invest Volume: 8 Issue: 2 Pages: 152-154
  • DOI: 10.1111/jdi.12573
  • Peer Reviewed / Open Access
• [Journal Article] High-carb or low-carb, that is a question (Commentary) (2017)
  • Author(s): Igawa H, Takamura T
  • Journal Title: Diabetol Int Volume: 8 Issue: 1 Pages: 1-3
  • DOI: 10.1007/s13340-016-0296-5
  • Open Access
• [Journal Article] Rapid response of the steatosis-sensing hepatokine LECT2 during diet-induced weight cycling in mice. (2016)
  • Author(s): K Chikamoto, H Misu, H Takayama, A Kikuchi, KA Ishii, F Lan, N Takata, N Tajima-Shirasaki, Y Takeshita, H Tsugane, S Kaneko, S Matsugo, T Takamura.
  • Journal Title: Biochem Biophys Res Commun Volume: 478 Issue: 3 Pages: 1310-1316
  • DOI: 10.1016/j.bbrc.2016.08.117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Fat-free mass and calf circumference as body composition indices to determine non-exercise activity thermogenesis in patients with diabetes (2016)
  • Author(s): Y. Isobe, M. Sakurai, Y. Kita, Y. Takeshita, H. Misu, S. Kaneko, T. Takamura
  • Journal Title: J Diabetes Investig Volume: 7 Issue: 3 Pages: 352-358
  • DOI: 10.1111/jdi.12421
  • NAID: 120005682647
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pleiotropic effects of sitagliptin versus voglibose in patients with type 2 diabetes inadequately controlled via diet and/or a single oral antihyperglycemic agent: a multicenter, randomized trial (2016)
  • Author(s): Matsushima Y, Takeshita Y, Kita Y, Otoda T, Kato K, Toyama-Wakakuri H, Akahori H, Shimizu A, Hamaguchi E, Nishimura Y, Kanamori T, Kaneko S, Takamura T
  • Journal Title: BMJ Open Diabetes Res Care Volume: 4 Issue: 1 Pages: e000190-e000190
  • DOI: 10.1136/bmjdrc-2015-000190
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Once-weekly glucagon-like peptide-1 receptor agonist dulaglutide significantly decreases glycated haemoglobin compared with once-daily liraglutide in Japanese patients with type 2 diabetes: 52 weeks of treatment in a randomized phase III study (2016)
  • Author(s): Odawara M, Miyagawa J, Iwamoto N, Takita Y, Imaoka T, Takamura T
  • Journal Title: Diabetes Obes Metab Volume: 18 Issue: 3 Pages: 249-257
  • DOI: 10.1111/dom.12602
  • Peer Reviewed / Open Access
• [Journal Article] Bending of a vertical cannula without alarm during insulin pump therapy as a cause of unexpected hyperglycemia: A Japanese issue? (2015)
  • Author(s): Kuroda K, Takeshita Y, Kaneko S, Takamura T
  • Journal Title: J Diabetes Investig Volume: 6 Issue: 6 Pages: 739-740
  • DOI: 10.1111/jdi.12357
  • NAID: 120005689372
  • Peer Reviewed / Open Access
• [Journal Article] Sitagliptin versus mitiglinide switched from mealtime dosing of a rapid-acting insulin analog in patients with type 2 diabetes: a randomized, parallel-group study (2015)
  • Author(s): Takeshita Y, Takamura T, Kita Y, Takazakura A, Kato K, Isobe Y, Kaneko S
  • Journal Title: BMJ Open Diabetes Res Care Volume: 3 Issue: 10 Pages: 974-983
  • DOI: 10.1111/dom.12534
  • NAID: 120005774893
  • Peer Reviewed / Open Access
• [Journal Article] Renoprotective effects of atorvastatin compared with pravastatin on progression of early diabetic nephropathy (2015)
  • Author(s): Takazakura A, Sakurai M, Bando Y, Misu H, Takeshita Y, Kita Y, Shimizu A, Hayakawa T, Kato K, Kaneko S, Takamura T
  • Journal Title: J Diabetes Investig Volume: 6 Issue: 3 Pages: 346-353
  • DOI: 10.1111/jdi.12296
  • NAID: 120005819637
  • Peer Reviewed / Open Access
• [Journal Article] Physiological roles of peroxido-vanadium complexes: Leitmotif as their signal transduction pathway (Review) (2015)
  • Author(s): Matsugo S, Kanamori K, Sugiyama H, Misu H, Takamura T
  • Journal Title: J Inorg Biochem Volume: Epub 2015 Feb 25 Pages: 93-98
  • DOI: 10.1016/j.jinorgbio.2015.02.008
  • Peer Reviewed / Open Access
• [Journal Article] Whole exome sequencing combined with integrated variant annotation prediction identifies asymptomatic Tangier disease with compound heterozygous mutations in ABCA1 gene. (2015)
  • Author(s): Tada H, Kawashiri MA, Nohara A, Saito R, Tanaka Y, Nomura A, Konno T, Sakata K, Fujino N, Takamura T, Inazu A, Mabuchi H, Yamagishi M, Hayashi K.
  • Journal Title: Atherosclerosis. Volume: 240 Issue: 2 Pages: 324-9
  • DOI: 10.1016/j.atherosclerosis.2015.04.003
  • Peer Reviewed / Open Access
• [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] 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] Response to Importance of confounding factors in assessing fatty acid compositions in patients with non-alcoholic 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 Issue: 6 Pages: 1773-1773
  • DOI: 10.1111/liv.12755
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] 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] 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] 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] Remodeling of nutrient homeostasis by unfolded protein response. (2014)
  • Author(s): Takamura T
  • Journal Title: Diabetes Volume: 63 Issue: 3 Pages: 841-3
  • DOI: 10.2337/db13-1721
  • NAID: 120005411651
  • Peer Reviewed
• [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
• [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
• [Presentation] Effect of ursodeoxycholic acid added to dipeptidyl peptidase-4 inhibitor on GLP-1 secretion and glucose tolerance in subjects with type 2 diabetes (2017)
  • Author(s): Kosuke Shima, Yumie Takeshita, Hirofumi Misu, Tsuguhito Ota, Toshinari Takamura
  • Organizer: The Keystone Symposia Conference C1: Bile Acid Receptors as Signal Integrators in Liver and Metabolism,
  • Place of Presentation: モントレー（カリフォルニア、米国）
  • Year and Date: 2017-03-06
  • Int'l Joint Research
• [Presentation] Regulation of Insulin Signaling Molecules by Selective Autophagy in Mice with Proteasome Dysfunction and Starvation (2017)
  • Author(s): Akihiro Kikuchi, Hirobumi Igawa, Yumiko Tahira, Toshinari Takamura
  • Organizer: Keystone Symposia 2017 Conference (J3: Diabetes)
  • Place of Presentation: Keystone, Colorado, USA
  • Year and Date: 2017-01-24
  • Int'l Joint Research
• [Presentation] Insulin receptor substrate 1 is selectively degraded by starvation-induced autophagy (2017)
  • Author(s): Hirobumi Igawa, Akihiro Kikuchi, Yumiko Tahira, Toshinari Takamura
  • Organizer: Keystone Symposia 2017 Conference (J4: Obesity and adipose tissue biology)
  • Place of Presentation: Keystone, Colorado, USA
  • Year and Date: 2017-01-23
  • Int'l Joint Research
• [Presentation] 日本人NAFLDの病理におよぼす高血糖の重要性（ランチョンセミナー） (2016)
  • Author(s): 篁 俊成
  • Organizer: 第31回日本糖尿病合併症学会
  • Place of Presentation: 仙台
  • Year and Date: 2016-10-08
  • Invited
• [Presentation] 【新時代の慢性肝疾患研究】 肝臓代謝リモデリングによる栄養恒常性の維持と破綻（ワークショップ） (2016)
  • Author(s): 篁 俊成
  • Organizer: 第48回日本臨床分子形態学会学術集会
  • Place of Presentation: 熊本
  • Year and Date: 2016-09-23
  • Invited
• [Presentation] 肝臓のエネルギー代謝調節におけるタンパク質分解系の意義（ワークショップ） (2016)
  • Author(s): 篁 俊成
  • Organizer: 第3回肝臓と糖尿病・代謝研究会
  • Place of Presentation: 金沢
  • Year and Date: 2016-07-16
  • Invited
• [Presentation] 肝と代謝制御 セレノプロテインPの運動抵抗性における意義と骨格筋型受容体の同定（シンポジウム） (2016)
  • Author(s): 篁 俊成、御簾 博文
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-05-21
  • Invited
• [Presentation] 新たな糖尿病合併症に迫る 「Diabetic Cirrhosis Revisited」 (2015)
  • Author(s): 篁 俊成
  • Organizer: 第30回日本糖尿病合併症学会
  • Place of Presentation: 名古屋国際会議場（愛知県、名古屋市）
  • Year and Date: 2015-11-27
  • Invited
• [Presentation] 栄養バランスから再考する2型糖尿病の病態と治療 (2015)
  • Author(s): 篁 俊成
  • Organizer: 第89回日本糖尿病学会中部地方会
  • Place of Presentation: 静岡県コンベンションアーツセンター（グランシップ）（静岡県、静岡市）
  • Year and Date: 2015-10-04
  • Invited
• [Presentation] 肥満に伴う肝障害の基礎と臨床 (2015)
  • Author(s): 篁 俊成
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 名古屋国際会議場（愛知県、名古屋市）
  • Year and Date: 2015-10-02
  • Invited
• [Presentation] 基礎・臨床研究と地域連携で挑む糖尿病医療 (2015)
  • Author(s): 篁 俊成
  • Organizer: 第13回日本予防医学会学術総会
  • Place of Presentation: フレンドパーク石川（石川県勤労者福祉文化会館）（石川県、金沢市）
  • Year and Date: 2015-06-20
  • Invited
• [Presentation] Efficacy and Safety of Once-weekly Dulaglutide versus Once-daily Liraglutide in Japanese patients with Type 2 Diabetes (2015)
  • Author(s): Toshinari Takamura, Jun-ichiro Miyagawa, Masato Odawara, Yasushi Takita, Noriyuki Iwamoto, Takeshi Imaoka
  • Organizer: The 75th Scientific Sessions American Diabetes Association (ADA)
  • Place of Presentation: Boston Convention & Exhibition Center（ボストン、米国）
  • Year and Date: 2015-06-05
  • Int'l Joint Research
• [Presentation] 栄養代謝経路間クロストークを介した肝臓代謝リモデリング (2015)
  • Author(s): 篁 俊成
  • Organizer: 第2回肝臓と糖尿病・代謝研究会
  • Place of Presentation: 山口県国際総合センター（山口県、下関市）
  • Year and Date: 2015-05-23
  • Invited
• [Presentation] インクレチン療法―現状と未来への可能性 「インクレチンの多面的作用 NASH・NAFLDを改善するか?」 (2015)
  • Author(s): 篁 俊成, 竹下 有美枝
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 山口県国際総合センター（山口県、下関市）
  • Year and Date: 2015-05-21
  • Invited
• [Presentation] Palmitate and eicosapentaenoic acid oppositely regulate selenoprotein P gene expression in H4IIEC hepatocytes (2015)
  • Author(s): Takamura T, Natsumi N, Takayama H, Misu H, Kaneko S
  • Organizer: Keystone Symposia, Liver Metabolism and Nonalcoholic Fatty Liver Disease (NAFLD) (X8)
  • Place of Presentation: Fairmont Chateau Whistler (Whistler, British Columbia, Canada)
  • Year and Date: 2015-03-25
• [Presentation] ヘパトカイン解析から見えてきた糖尿病の新病態 (2015)
  • Author(s): 篁 俊成
  • Organizer: 第49回糖尿病学の進歩
  • Place of Presentation: ホテルグランヴィア岡山（岡山県、岡山市）
  • Year and Date: 2015-02-21
  • Invited
• [Presentation] 肝臓代謝リモデリングによる栄養恒常性の維持と破綻 (2014)
  • Author(s): 篁 俊成
  • Organizer: 第35回日本肥満学会、ランチョンセミナー
  • Place of Presentation: フェニックスシーガイアリゾート コンベンションセンター（宮崎県、宮崎市）
  • Year and Date: 2014-10-25
  • Invited
• [Presentation] 食と肥満による肝臓代謝リモデリング (2014)
  • Author(s): 篁 俊成
  • Organizer: 第35回日本肥満学会、シンポジウム
  • Place of Presentation: フェニックスシーガイアリゾート コンベンションセンター（宮崎県、宮崎市）
  • Year and Date: 2014-10-25
  • Invited
• [Presentation] A satiety-induced hepatokine LECT2 causes skeletal muscle insulin resistance via JNK activation (2014)
  • Author(s): Takamura T
  • Organizer: 2014 International Conference on Diabetes and Metabolism (ICDM)
  • Place of Presentation: Kintex Ilsan (Gyeonggido, Korea)
  • Year and Date: 2014-10-18
  • Invited
• [Presentation] Remodeling of nutrient homeostasis by obesity-associated proteasome dysfunction (2014)
  • Author(s): Takamura T
  • Organizer: 2014 International Conference on Diabetes and Metabolism (ICDM)
  • Place of Presentation: Kintex Ilsan (Gyeonggido, Korea)
  • Year and Date: 2014-10-17
  • Invited
• [Presentation] 肝臓から考える糖尿病に対する食事・運動療法 (2014)
  • Author(s): 篁 俊成
  • Organizer: 第29回日本糖尿病合併症学会、シンポジウム
  • Place of Presentation: 都市センターホテル（東京都、千代田区）
  • Year and Date: 2014-10-03
  • Invited
• [Presentation] ヘパトカインを介した肝臓-骨格筋連関によるエネルギー代謝調節 (2014)
  • Author(s): 篁 俊成
  • Organizer: 第57回 日本糖尿病学会年次学術集会、シンポジウム
  • Place of Presentation: 大阪国際会議場（大阪府、大阪市）
  • Year and Date: 2014-05-23
  • Invited
• [Book] Ectopic Fat Accumulation in the Liver and Glucose Homeostasis (in Musculoskeletal Disease Associated with Diabetes Mellitus, Ed by Masaaki Inaba)) (2016)
  • Author(s): Toshinari Takamura, Hirofumi Misu, Shuichi Kaneko
  • Total Pages: 296
  • Publisher: Springer
• [Remarks] 金沢大学大学院医学系研究科 内分泌・代謝内科学分野
  • URL: http://metabology.w3.kanazawa-u.ac.jp
• [Remarks] 金沢大学大学院医学系研究科 内分泌・代謝内科学分野
  • URL: http://metabology.w3.kanazawa-u.ac.jp
• [Remarks] 金沢大学医薬保健研究域医学系 包括的代謝学分野
  • URL: http://metabology.w3.kanazawa-u.ac.jp/