Regulation of hepatic insulin sensitivity by CREB

描述（由申请人提供）：本研究的目的是检查转录因子CREB如何调节肝脏胰岛素敏感性。在禁食期间，CREB诱导肝脏中的致瘤基因，这些基因在餐后对胰岛素的反应中被抑制。拟议的研究将测试以下假设：在禁食期间，CREB通过激活胰岛素信号传导途径中的基因（包括胰岛素受体IRS-2）的表达，启动肝脏有效停止胰岛素生成。具体来说，我将研究CREB依赖的胰岛素途径基因转录的分子机制，以及这种调节回路如何调节葡萄糖稳态。我将评估CREB，其共激活因子TORC 2和Foxo转录因子在原代肝细胞中通过RNAi介导的敲低转录这些基因的需求。我还将通过体内腺病毒感染急性敲低CREB、TORC 2和Foxo，然后测量空腹血糖水平、胰岛素耐受性和肝葡萄糖输出，来研究该途径对空腹肝胰岛素敏感性的影响。这项研究将有助于了解空腹与进食状态下调节葡萄糖输出和储存之间平衡的机制。

DESCRIPTION (provided by applicant): The objective of this study is to examine how the transcription factor CREB modulates hepatic insulin sensitivity. During fasting, CREB induces gluconeogenic genes in liver, which are repressed in response to insulin after a meal. The proposed studies will test the hypothesis that during fasting CREB primes the liver for efficient cessation of gluconeogenesis by activating expression of genes in the insulin signaling pathway, including the insulin receptor IRS-2. Specifically, I will investigate the molecular mechanisms of CREB- dependent transcription of insulin pathway genes and how this regulatory loop modulates glucose homeostasis. I will assess the requirements of CREB, its co-activator TORC2, and Foxo transcription factors for transcription of these genes by RNAi-mediated knockdown in primary hepatocytes. I will also examine the effects of this pathway on fasting hepatic insulin sensitivity by acute knockdown of CREB, TORC2 and Foxo by adenovirus infection in vivo followed by measurements of fasting blood glucose levels, insulin tolerance, and hepatic glucose output. This study will contribute to an understanding of the mechanisms regulating the balance between glucose output and storage in fasted versus fed states.