PROTEOMIC STUDY OF HEPATIC METABOLISM REGULATED BY HYPOTHALAMIC PATHWAYS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 下丘脑内侧基底核(MBH)在控制肝脏葡萄糖稳态中起着关键作用。MBH感知循环中的营养物质，如葡萄糖和脂肪酸，以及激素，如瘦素和胰岛素，从而评估有机体的能量状态。当营养素和胰岛素的循环水平在餐后状态上升时，从MBH下降的通路被激活，肝脏葡萄糖产生(HGP)被抑制。在胰岛素抵抗(IR)状态下，胰岛素不能抑制肝脏葡萄糖生成(HGP)，部分原因是HGP失去了对MBH的控制。由于这些中心通路的激活，在外周组织中发生的分子事件还知之甚少。这项建议的总体目标是利用来源的高灵敏度、高分辨率的LC-MS定量蛋白质组学来确定MBH激活引起的总组织和亚细胞区段(包括胞浆、线粒体和膜部分)中蛋白质水平的差异。我们的目标是通过应用先进的蛋白质组学技术来鉴定几种亚细胞提取物中蛋白质丰度的差异以及丝氨酸/苏氨酸磷酸化的差异。我们的目标是确定肝组织中控制脂肪和葡萄糖代谢的关键分子途径。这些研究有可能促进发现新的治疗靶点，降低胰岛素抵抗，避免或改善2型糖尿病。蛋白质组学数据将为NIH R01的应用以及未来的出版提供初步数据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The medio-basal hypothalamus (MBH) plays a pivotal role in the control of hepatic glucose homeostasis. The MBH senses circulating nutrients like glucose and fatty acids as well as hormones like leptin and insulin and thus assesses the energy state of the organism. When circulating levels of nutrients and insulin are rising during the postprandial state, pathways descending from the MBH are activated and hepatic glucose production (hGP) is suppressed. In the insulin resistant (IR) state insulin fails to suppress hepatic glucose production (hGP) which is partly explained by a loss of the MBH control of hGP. The molecular events that take place in peripheral tissues by the activation of these central pathways are poorly understood. The overall goal of this proposal is to utilize high sensitivity, high resolution LC-MS quantitative proteomics from the resource to identify differences in protein levels in total tissue as well as subcellular compartments (including cytosolic, mitochondria and membrane fractions) that are induced by the activation of the MBH. We aim to identify differences in protein abundances as well as serine/threonine phosphorylation differences in several subcellular extracts by applying the advanced proteomics technologies. Our goal is to identify key molecular pathways in liver tissue that exert control of lipid and glucose metabolism. These studies have the potential to facilitate the discovery of new therapeutic targets that decrease insulin resistance and avert or ameliorate type 2 diabetes. The proteomic data will serve the preliminary data for NIH R01 application as well as for future publications.