Research Abstract


Real-time monitoring in three-dimensional hepatocytes reveals that insulin acts as a synchronizer for liver clock

2012年6月1日 Scientific Reports 2 : 439 doi: 10.1038/srep00439


山宿 大介1、稲垣 貴彦2、春間 智統2、大久保 慎吾2、片岡 裕太郎2、小林 悟2、池上 啓介2、Thomas Laurent2、小島 知子1、納富 恵至1、橋本 誠一1 & 小田 裕昭2

  1. アステラス製薬株式会社 創薬研究本部 分子医学研究所
  2. 名古屋大学大学院生命農学研究科

Resetting the peripheral clock and understanding the integration between the circadian rhythm and metabolic pathways are fundamental questions. To test whether insulin acts as a synchronizer for the hepatic clock by cell-autonomous mechanisms, the phase-resetting capabilities of insulin were investigated in cultured hepatic cells. We provide evidence that three-dimensional (3D) cell culture conditions that preserve the differentiated state of primary hepatocytes sustained the robustness of the molecular clock, while this robustness rapidly dampened under classical monolayer cell culture conditions. Herein, we established a 3D cell culture system coupled with a real-time luciferase reporter, and demonstrated that insulin directly regulates the phase entrainment of hepatocyte circadian oscillators. We found that insulin-deficient diabetic rats had a pronounced phase advance in their hepatic clock. Subsequently, a single administration of insulin induced phase-dependent bi-directional phase shifts in diabetic rat livers. Our results clearly demonstrate that insulin is a liver clock synchronizer.