Direct and Indirect Effects of Insulin on Target Tissues to Decrease Glucose

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08502
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Chiba University
• Principal Investigator: Ono Hiraku 千葉大学, 大学院医学研究院, 准教授 (10570616)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: インスリン / ブドウ糖 / 肥満 / 摂食

Outline of Final Research Achievements

Insulin and glucose are maintaining metabolic homeostasis of whole body via their signals in multiple target organs, while the precise mechanisms are unclear. We performed artificial bidirectional interventions on insulin/glucose signaling in their target tissues. Transcriptional factor FoxO1 generally antagonizes insulin signaling, because insulin inhibits its transcriptional activity. In contrast, we found that constitutive activation of FoxO1 in adipocytes rather enhances glucose uptake and lipogenesis without enhancing cell proliferation, suggesting that FoxO1 activation in adipose tissue is able to improve metabolism without a risk of tumorigenesis. Moreover, we found an inhibition of sodium-glucose cotransporter 2 (SGLT2) in the central nervous system enhances food intake, suggesting that central SGLT2 has a role to sense glucose in the brain to regulate food intake.

Free Research Field

肥満，糖尿病，代謝

Academic Significance and Societal Importance of the Research Achievements

糖尿病や肥満の根治療法は未だ発見されておらず，これはインスリンが糖代謝をつかさどる仕組みや，体重が一定に維持される仕組みが未解明であるからに他ならない。本研究で見出された，脂肪組織でFoxO1を活性化させると腫瘍化のリスクなく糖代謝が改善することや，脳SGLT2が摂食調節に関与しているという知見は，新たな糖尿病や肥満の治療法を発見できる糸口になりうる成果と考えている。