Analysis and identification of microRNA that regulates insulin signal pathway

• Project/Area Number: 16K09760
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kumamoto University
• Principal Investigator: IGATA MOTOYUKI 熊本大学, 病院, 助教 (40599099)
• Co-Investigator(Kenkyū-buntansha): 荒木 栄一 熊本大学, 大学院生命科学研究部(医), 教授 (10253733)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: microRNA / インスリンシグナル / 糖尿病

Outline of Final Research Achievements

We focused on miR-222, the expression of which was increased in the livers of high fat/high sucrose diet-fed mice injected with gold thioglucose (G+HFHSD). Overexpression of miR-222 in primary mouse hepatocytes attenuated Akt phosphorylation induced by insulin, indicating that miR-222 negatively regulates insulin signaling. As per in silico analysis, miR-222 potentially binds to the 3′ untranslated region (3′ UTR) of the IRS-1 gene, a key insulin signaling molecule. In fact, IRS-1 protein expression was decreased in the livers of G+HFHSD-fed mice. We further confirmed a direct interaction between miR-222 and the 3′ UTR of IRS-1 via luciferase assays. Our findings suggest that up-regulation of miR-222 followed by reduction in IRS-1 expression may be a viable mechanism of insulin resistance in the liver.

Academic Significance and Societal Importance of the Research Achievements

本邦を含め世界中で肥満、糖尿病患者数は増加の一途を辿り、現社会における大きな問題の一つとなっている。肥満、糖尿病を予防・治療していくためには、その病態理解が重要であることは言うまでもない。近年、蛋白に翻訳されないnon-coding RNAが注目されており、我々はインスリン抵抗性とmicro RNAに注目し研究を行い、肝におけるインスリン抵抗性発症の一つの機序を明らかにした。microRNAは今後、疾患のバイオマーカーや治療への応用も期待されており、今後の研究が期待される。

Research Products

• [Journal Article] Identification of microRNA that represses IRS-1 expression in liver. (2018)
  • Author(s): Ono K, Igata M, Kondo T, Kitano S, Takaki Y, Hanatani S, Sakaguchi M, Goto R, Senokuchi T, Kawashima J, Furukawa N, Motoshima H, Araki E
  • Journal Title: PLoS One Volume: 13 Issue: 1 Pages: 0191553-0191553
  • DOI: 10.1371/journal.pone.0191553
  • Peer Reviewed / Open Access
• [Presentation] Obesity-induced microRNA-222 impairs insulin signaling through the repression of IRS-1 expression in hepatocytes. (2017)
  • Author(s): Ono K, Igata M, Kondo T, Kitano S, Takaki Yuki, Hanatani S, Goto R, enokuchi T, Kawashima J, Furukawa N, Motoshima H, ArakiE
  • Organizer: 53th EASD Annual Meeting
  • Int'l Joint Research
• [Presentation] 肝臓においてIRS-1発現抑制を介してインスリンシグナルを制御するmicroRNAの同定. (2017)
  • Author(s): 小野 薫, 井形元維, 近藤龍也, 高木優樹, 北野さやか, 後藤理英子, 瀬ノ口隆文, 河島淳司, 荒木 栄一
  • Organizer: 第60回日本糖尿病学会総会
• [Presentation] miR-222は肝臓においてIRS-1発現抑制を介してインスリンシグナルを制御する (2017)
  • Author(s): 小野 薫, 井形元維, 近藤龍也, 高木優樹, 北野さやか, 後藤理英子, 瀬ノ口隆文, 河島淳司, 荒木 栄一
  • Organizer: 第55回日本糖尿病学会九州地方会