Transcriptional coactivators and hepatic glucose production

描述（由申请方提供）：在进食期间和餐后状态下，血糖水平升高会迅速增加胰岛素分泌并减少胰高血糖素分泌，导致葡萄糖释放受到抑制并将葡萄糖作为糖原储存在肝脏中。在吸收后状态和早期禁食期间，肝糖原分解被激活以维持正常。相反，糖原储备耗尽后，在长时间禁食期间，糖原异生在维持血糖水平方面起主导作用。与此模型相反，对人类的研究表明，即使在过量胰岛素的情况下，胰岛素生成也不会完全受到抑制。这些数据表明，肝糖原生成的一个组成部分可能是正常不受调节的，据估计，多达40-70%的新合成的糖原是通过糖原生成途径形成的。我们认为，p300通常驱动基础肝再生和糖原合成，因为肝p300的耗竭导致糖原含量减少和相对低血糖。相反，高脂饮食（HFD）喂养显着和迅速增加p300蛋白水平。考虑到不适当的肝再生是肥胖和糖尿病患者高血糖的主要原因，HFD喂养对p300的早期诱导可能是肝再生升高的原因。了解HFD喂养诱导早期p300的机制将被证明对于了解T2 DM中不受调节的肝脏葡萄糖产生的基本机制是非常宝贵的。因此，我们提出了三个具体的目标来解决这些问题：1）确定FOXO 1和p300在调节肝葡萄糖产生（HGP）中的相互作用：2）确定p300通过肝细胞生成和糖原生成对肝糖原合成的影响;和3）确定喂食HFD的小鼠肝脏中p300蛋白的早期诱导机制，并与慢性肥胖小鼠模型（ob/ob）中的p300表达进行比较。

DESCRIPTION (provided by applicant): During feeding and in the post-prandial state, elevated blood glucose levels promptly increase the secretion of insulin and decrease the secretion of glucagon, leading to the suppression of glucose release and storage of glucose as glycogen in the liver. In the post-absorptive state and during early fasting, hepatic glycogenolysis is activated to maintain euglycemia. In contrast, gluconeogenesis plays a dominant role in maintaining blood glucose levels during prolonged fasting after glycogen stores are depleted. Contrary to this model, studies in humans have shown that gluconeogenesis is not completely suppressed even in the presence of excess insulin. These data suggest that a component of hepatic gluconeogenesis may be normally unregulated, and it is estimated that as much as 40-70% of newly synthesized glycogen is formed via the gluconeogenic pathway. We suggest that p300 normally drives basal gluconeogenesis and glycogen synthesis because depletion of hepatic p300 leads to reduced glycogen content and relative hypoglycemia. In contrast, high-fat diet (HFD) feeding markedly and promptly increases p300 protein levels. Given that inappropriate hepatic gluconeogenesis is a major cause of hyperglycemia in obese and diabetic patients, the early induction of p300 by HFD feeding may be responsible for elevated hepatic gluconeogenesis. Understanding the mechanism of early p300 induction by HFD feeding will prove invaluable for understanding basic mechanisms underlying unregulated hepatic glucose production in T2DM. We therefore propose three specific aim to address these questions: 1) To define the interaction between FOXO1 and p300 in regulation of hepatic glucose production (HGP); 2) To determine the effect of p300 on hepatic glycogen synthesis through gluconeogenesis and glycogenesis; and 3) To define the mechanism of early induction of p300 protein in the liver of mice fed a HFD and compare to p300 expression in a chronic obesity mouse model (ob/ob).