Defining the neurocircuit activated by the VMH to control energy expenditure.

项目摘要 虽然健康人的体重受到严格控制，但肥胖是由体内平衡失调造成的 保护个体免受代谢性疾病侵袭的机制。肥胖已经困扰着大约1亿人 在这个国家，人们每年要花费大约2000亿美元。因此，当务之急是我们找到 在这个问题失控之前，更好地治疗肥胖症。大脑蕴藏着未被开发的潜能 肥胖症治疗的途径。虽然很明显，神经机制可以戏剧性地转移能量 动态平衡，到目前为止，这些机制还没有得到很好的描述。专门的神经元检测变化 处于能量状态。因为大脑耗尽了身体几乎四分之一的营养，所以特别是 对大脑来说，保持能量水平在正常范围内是很重要的。因此，有没有未被发现的，或者没有 完全被发现的大脑中维持能量动态平衡的内置系统。 最近的研究旨在了解大脑中不同组细胞参与的功能 代谢功能的个别方面。这是最近被发现的一个关键领域的情况 大脑被称为腹内侧部下丘脑。我们已经发表了一些论文来识别这个细胞中的一组细胞 大脑区域对低血糖的反调节是必不可少的，这是糖尿病治疗的关键因素。这些细胞 与其他通过刺激能量而对能量平衡至关重要的物质混合在同一区域 支出。去掉以垂体腺苷环化酶激活多肽为中心的神经肽 下丘脑腹内侧会导致肥胖。因为与腹内侧部没有直接联系 下丘脑具有外周器官靶点，这些功能必须通过下游部位来控制 对脑下垂体腺苷环化酶激活多肽有反应。 在这项提议中，我们的目标是确定解剖和细胞靶点在 下丘脑腹内侧神经元投射。我们的初步数据显示，下丘脑腹内侧 神经元只投射到少数几个部位。这些突起特别覆盖视前区的尾部。 区域，一个对能源支出控制至关重要的区域。我们将使用遗传小鼠模型与 AAV驱动的功能获得或丧失实验，以测试传递燃料的饮食信号的假设 神经肽参与下丘脑腹内侧和视前区作用的充分性 含有神经肽受体的抑制性神经元。我们将定义饮食信号 需要下丘脑腹内侧神经肽和这些细胞的下游通讯。我们会 然后确定需要神经肽受体和通讯激活的下游区域 被这些细胞。然后，我们将确定视前区内含有神经肽的抑制细胞 受体及其参与的外周活动，通过能量消耗来支持能量平衡。

PROJECT ABSTRACT While body weight is tightly regulated in healthy individuals, obesity results from failed homeostatic mechanisms that protect individuals from metabolic disease. Obesity already plagues approximately 100 million people and costs approximately $200 billion dollars annually in this country. Thus, it is imperative that we find better ways to treat obesity before this problem gets out of control. The brain contains unexplored potential avenues for obesity treatment. While it has been clear that neural mechanisms can dramatically shift energy homeostasis, these mechanisms have been poorly described to this point. Specialized neurons detect changes in energy status. Because the brain exhausts almost a quarter of all nutrients in the body, it is especially important for the brain to keep energy levels in a normal range. Therefore, there are undiscovered, or not completely discovered, built-in systems into the brain that maintain energy homeostasis. Recent studies have aimed to understand the function of distinct sets of cells in the brain involved in individual aspects of metabolic function. This has recently been revealed to be the case for a key area of the brain called the ventromedial hypothalamus. We have published papers that identify a set of cells within this brain area is essential for hypoglycemic counterregulation, a critical factor for diabetes treatment. These cells are intermingled in the same area with others that are essential for energy balance by stimulating energy expenditure. Removing the neuropeptide pituitary adenylate cyclase activating polypeptide centered on the ventromedial hypothalamus induces obesity. Because there are no direct connections from the ventromedial hypothalamus with peripheral organ targets, these functions must be controlled through a downstream site to that responds to pituitary adenylate cyclase activating polypeptide. In this proposal, we aim to identify both the anatomical and the cellular targets in the regions that ventromedial hypothalamus neurons project. Our preliminary data indicate that ventromedial hypothalamus neurons only project to a few sites. These projections particularly overlay with the caudal divisions of the preoptic area, a region critical to energy expenditure control. We will employ genetic mouse models in conjunction with AAV-driven gain or loss of function experiments to test the hypothesis that dietary signals that communicate fuel adequacy to engage the neuropeptide in the ventromedial hypothalamus and action within the preoptic area on neurons that are inhibitory and contain the receptor for the neuropeptide. We will define the dietary signals that require the ventromedial hypothalamus neuropeptide and downstream communication by these cells. We will then determine the downstream regions that requires activation by the neuropeptide receptor and communication by these cells. Then, we will identify the inhibitory cells within the preoptic area that contain the neuropeptide receptor and the peripheral actions they engage to support energy balance through energy expenditure.