肠Ghrelin信号改变通过“肠-脑-肝”轴对糖-脂代谢的调节机制

It is well established that brain-gut-peptide hormones, such as glucagon-like peptide (GLP-1) and Ghrelin, are associated with energy homeostasis and insulin resistance in vivo. Although the metabolic effects of these peptide hormones have been reported, to date, it is unknown whether these peptide signals are mediated through a gut-brain - liver neuronal network to control glucose homeostasis in vivo. In this study, the effects of Ghrelin, as one of these hormones, on glucose kinetics will be assessed by association intraduodenal infusions with intracerebroventricular infusions and euglycemic-hyperinsulinemic clamp studies based on three tracer-dilution methodologies as well as molecular biology methods. In addition, the effects of central Ghrelin on glucose kinetics will be also assessed by Ghrelin knockout mice. Finally, the underlying gut-brain-liver neuronal network and molecule mechanisms of Ghrelin signaling will be further revealed. These data will highlight a previously unappreciated role of both duodenal and central Ghrelin signaling in regulation of glucose and lipid homeostasis and insulin sensitivity.

近年的研究表明脑肠肽类激素如胰高血糖素样肽-1、Ghrelin等与机体能量平衡和胰岛素抵抗密切相关。尽管对这些激素的外周生物学效应已有较多的了解，但对其信号在体内"肠-脑-肝"之间的转导对代谢的调节机制，目前并不清楚。本研究以Ghrelin为代表,将十二指肠导管植入灌流术、中枢第三脑室微量给药系统和扩展胰岛素钳夹技术相结合, 并利用3-[3H]葡萄糖、2-脱氧-3H葡萄糖和14C乳酸盐三种示踪技术及分子生物学方法，分别探讨了肠Ghrelin信号变化对机体糖-脂代谢的动力学影响。在此基础上，进一步分析了肠Ghrelin信号对机体糖-脂代谢影响的可能信号转导通路及其分子机制。此外，通过神经离断的方法，探讨了Ghrelin信号传递的可能通路。本课题的实施对于从体内代谢组学的角度，深入研究脑肠肽类激素作用的分子生物学靶点，全面诠译该类激素通过"肠-脑-肝"轴对机体代谢进行调控的机制具有重要的意义。

近年的研究表明脑肠肽类激素如胰高血糖素样肽-1、Ghrelin等与机体能量平衡和胰岛素抵抗密切相关。尽管对这些激素的外周生物学效应已有较多的了解，但对其信号在体内“肠-脑-肝”之间的转导对代谢的调节机制，目前并不清楚。本研究以Ghrelin为代表,将十二指肠导管植入灌流术、中枢第三脑室微量给药系统和扩展胰岛素钳夹技术相结合,并利用3-[3H]葡萄糖、2-脱氧-3H葡萄糖和14C乳酸盐三种示踪技术及分子生物学方法，分别探讨了肠Ghrelin信号变化对机体糖-脂代谢的动力学影响。该研究基本按计划完成了肠Ghrelin信号对肝糖代谢的影响、其经“肠-脑-肝轴”途径的作用机制及这一作用对肝糖变化的肝糖异生及胰岛素信号系统的作用机制。在此基础上，进一步分析了肠Ghrelin信号对Ghrelin信号传递的可能通路。