Glucosensing neurons in health, obesity & diabetes

描述(申请人提供)：本研究旨在研究胰岛素和瘦素对下丘脑弓状核(ARC)葡萄糖敏感神经元(GSNs)葡萄糖敏感性的影响。总体目标是清楚地了解(A)ARC GSNs的葡萄糖敏感性如何受到环境中胰岛素和瘦素水平的调节，以及(B)肥胖和2型糖尿病(T2 DM)中这些神经元信号的功能障碍信号通路如何改变ARC GSNs的功能。该提案中的两个假设直接解决了这些问题。假设一是胰岛素和瘦素调节ARC GSNs的葡萄糖敏感性。假设I的推论是，肥胖和T2 DM期间发生的胰岛素和瘦素信号功能障碍与ARC GSNs的葡萄糖敏感性受损有关。假设II一氧化氮(NO)信号转导通路是葡萄糖、胰岛素和瘦素调节ARC GSNs的汇聚点。本文提出的第一组实验将确定在胰岛素和瘦素存在的情况下ARC GNSS的葡萄糖浓度响应关系。我们还将探索葡萄糖、胰岛素和瘦素之间相互作用的细胞途径，以便了解任何反应性变化背后的机制。然后，我们将确定肥胖症和2型糖尿病期间这些反应是否或如何改变。第二组实验将检验这一假设，即NO提供了一条新的信号转导途径，葡萄糖、胰岛素和瘦素信号在此汇聚。我们还将检验这一假设，即NO为我们所观察到的葡萄糖诱导的突触前神经活动调节提供了一种机制。这些研究将提供关于大脑整合整体能量状态信号的方式以及这一系统在肥胖和2型糖尿病期间如何改变的重要信息。这将有助于为现代世界的这些严重疾病开发新的有效治疗方法。

DESCRIPTION (provided by applicant): This proposal investigates the effects of insulin and leptin on the glucose sensitivity of glucose sensing neurons (GSNs) in the hypothalamic arcuate nucleus (ARC). The overall objective is to gain a clear understanding of (a) how the glucose sensitivity of ARC GSNs is regulated by ambient levels of insulin and leptin and (b) how the dysfunctional signaling pathways for these neuronal signals seen in obesity and type 2 diabetes mellitus (T2DM) alter the function of ARC GSNs. The 2 hypotheses in this proposal directly address these issues. Hypothesis I is that insulin and leptin modulate the glucose sensitivity of ARC GSNs. The corollary to hypothesis I is that the dysfunctional insulin and leptin signaling which occurs during obesity and T2DM contributes to the impaired glucose sensitivity of ARC GSNs. Hypothesis II is the nitric oxide (NO) signal transduction pathway is a point of convergence in the regulation of ARC GSNs by glucose, insulin and leptin. The first set of experiments proposed herein will define the glucose concentration response relationships for ARC GNSs in the presence of insulin and leptin. We will also explore the cellular pathways underlying the interactions between glucose, insulin and leptin so that the mechanisms that underlie any change in responsiveness can be understood. We will then determine whether or how the responses are altered during obesity and T2DM. The second set of experiments will examine the hypotheis that NO provides a novel signal transduction pathway at which glucose, insulin and leptin signaling converges. We will also test the hypothesis that NO provides a mechanism for the glucose-induced presynaptic modulation of neuronal activity which we have observed. These studies will provide important information regarding the way that the brain integrates signals of overall energy status and how this system is altered during obesity and T2DM. This will facilitate the development of new and effective treatments for these serious diseases of the modern world.