Mechanism of insulin-induced GLUT4 down-regulation through retromer inhibition

• Project/Area Number: 23591295
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Gunma University
• Principal Investigator: SHIBATA Hiroshi 群馬大学, 生体調節研究所, 准教授 (20235584)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: インスリン / 活性酸素 / レトロマー / 脂肪細胞 / NADPHオキシダーゼ / GLUT4 / GLUUT4 / レトロマー複合体 / タンパク分解

Research Abstract

Long term insulin stimulation causes GLUT4 depletion. This effect is caused mainly by accelerated lysosomal degradation of GLUT4. We show that insulin acutely dissociated retromer from the LDM membranes of 3T3-L1 adipocytes that was accompanied by disruption of the interaction of Vps35 with sortilin. This insulin effect was dependent on protein kinase CK2 but not PI3-kinase or Erk 1/2. Knockdown of Vps26 decreased GLUT4 to a level comparable with that with insulin stimulation for 4 h. Vps35 with a mutation in the CK2 phosphorylation motif was resistant to insulin-induced dissociation from the low density microsomal membrane, and its overexpression attenuated GLUT4 down-regulation with insulin. Insulin-generated hydrogen peroxide was an upstream mediator of the insulin action on retromer and GLUT4. These results suggested that insulin-generated oxidative stress switches the GLUT4 sorting direction to lysosomes through inhibition of the retromer function in a CK2-dependent manner.

Research Products

• [Journal Article] Prolonged insulin stimulation down-regulates GLUT4 through oxidative stress-mediated retromer inhibition by a protein kinase CK2-dependent mechanism in 3T3-L1 adipocytes. (2014)
  • Author(s): Ma J, Nakagawa Y, Kojima I, Shibata H
  • Journal Title: J Biol Chem Volume: 289 Issue: 1 Pages: 133-142
  • DOI: 10.1074/jbc.m113.533240
  • Peer Reviewed
• [Journal Article] Glucose promotes its own metabolism by acting on the cell-surface glucose-sensing receptor T1R3 (2014)
  • Author(s): Nakagawa Y, Ohtsu Y, Nagasawa M, Shibata H, Kojima I
  • Journal Title: Endocr J Volume: Vol.61 Pages: 119-131
  • NAID: 130004718269
  • URL: https://www.jstage.jst.go.jp/article/endocrj/61/2/61_EJ13-0431/_article
  • Peer Reviewed
• [Journal Article] A Novel Regulatory Function of Sweet Taste-Sensing Receptor in Adipogenic Differentiation of 3T3-L1 Cells (2013)
  • Author(s): Masubuchi, Y., Nakagawa, Y., Ma, J., Sasaki, T., Kitamura, T., Yamamoto, Y., Kurose, H., Kojima, I., Shibata, H.
  • Journal Title: PLoS ONE Volume: 8 Issue: 1 Pages: e54500-e54500
  • DOI: 10.1371/journal.pone.0054500
  • Peer Reviewed
• [Journal Article] Miglitol prevents diet-induced obesity by stimulating brown adipose tissue and energy expenditure independent of preventing the digestion of carbohydrates (2013)
  • Author(s): Sasaki T, Shimpuku M, Kitazumi T, Hiraga H, Nakagawa Y, Shibata H, Okamatsu-Ogura Y, Kikuchi O, Kim HJ, Fujita Y, Maruyama J, Susanti VY, Yokota-Hashimoto H, Kobayashi M, Saito M, Kitamura T
  • Journal Title: Endocr J Volume: Vol.60 Pages: 1117-1129
  • NAID: 130004770394
  • URL: https://www.jstage.jst.go.jp/article/endocrj/60/10/60_EJ13-0333/_article
  • Peer Reviewed
• [Presentation] 甘味刺激によるGs活性化は微小管脱重合とRho活性化を介して脂肪分化を抑制する (2013)
  • Author(s): 増渕洋祐,中川祐子,馬金輝,長澤雅裕,小島至,柴田宏
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本市
• [Presentation] Sweet taste receptor regulates adipogenesis through Gs-mediated microtubule disassembly and Rho activation in 3T3-L1 cells (2013)
  • Author(s): Masubuchi Y, Nakagawa Y, Ma J, Nagasawa M, Kojima I, Shibata H
  • Organizer: 73rd Scientific Session of American Diabetes Association
  • Place of Presentation: マコーミックプレイス・コンベンションセンター(米国シカゴ市)
• [Presentation] Sweet Taste Receptor Regulates Adipogenesis Through Gs-Mediated Microtubule Disassembly and Rho Activation in 3T3-L1 Cells (2013)
  • Author(s): Masubuchi Y, Nakagawa Y, Ma J, Nagasawa M, Kojima I, Shibata H
  • Organizer: 73rd Scientific Sessions of American Diabetes Association
  • Place of Presentation: マコーミックプレイス・コンベンションセンター（米国シカゴ市）
• [Presentation] 新規インスリン・シグナル分子PC-PLCによるNox4活性化機構 (2012)
  • Author(s): 馬金輝,小島至,柴田宏
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: パシフィコ横浜(横浜市)
• [Presentation] 甘味受容体による脂肪細胞分化抑制のシグナル機構 (2012)
  • Author(s): 増渕洋祐,中川祐子,馬金輝,小島至,柴田宏
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: パシフィコ横浜(横浜市)
• [Presentation] A novel regulatory function of sweet taste-sensing receptor in adipogenic differentiation of 3T3-L1 cells (2012)
  • Author(s): Masubuchi Y, Nakagawa Y, Ma J, Kojima I, Shibata H
  • Organizer: 72nd Scientific Session of American Diabetes Association
  • Place of Presentation: ペンシルベニア・コンベンションセンター(米国フィラデルフィア市)
• [Presentation] 新規インスリン・シグナル分子PC-PLCによるNox4活性化機構 (2012)
  • Author(s): 馬金輝，小島至，柴田宏
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] A Novel Regulatory Function of Sweet Taste-Sensing Receptor in Adipogenic Differentiation of 3T3-L1 Cells (2012)
  • Author(s): Masubuchi, Y., Nakagawa, Y., Ma, J., Kojima, I., Shibata, H.
  • Organizer: American Diabetes Association 72nd Scientific Sessions
  • Place of Presentation: ペンシルベニア・コンベンションセンター（米国フィラデルフィア市）
• [Presentation] ホスファチジルコリン特異的PLCは脂肪細胞における活性酸素産生とGLUT4分解のインスリン・シグナルとして機能する (2011)
  • Author(s): 馬金輝,小島至,柴田宏
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌市
• [Presentation] 脂肪細胞における甘味受容体の発現と機能 (2011)
  • Author(s): 増渕洋祐,中川祐子,馬金輝,小島至,柴田宏
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌市
• [Presentation] ホスファチジルコリン特異的PLCは脂肪細胞における活性酸素産生とGLUT4分解のインスリン・シグナル分子として機能する (2011)
  • Author(s): 馬金輝、 小島至、 柴田宏
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌市
• [Presentation] 脂肪細胞における活性酸素産生と GLUT4 分解を惹起するインスリン・シグナル機構 (2011)
  • Author(s): 柴田宏，馬金輝，小島至
  • Organizer: 生理学研究所研究会「超階層シグナル伝達研究の新展開」
  • Place of Presentation: 岡崎市
• [Remarks]
  • URL: http://www.imcr.gunma-u.ac.jp/lab/celphy/
• [Remarks] 群馬大学生体調節研究所
  • URL: http://www.imcr.gunma-u.ac.jp/