Astrocytic Target Mechanisms in Obesity

项目摘要 肥胖及其相关并发症给我们的社会带来了巨大的负担。但 这种疾病及其相关病理的潜在机制仍不清楚，有效的治疗方法是 仍然缺乏。肥胖症的核心是能量摄入和能量消耗之间的不平衡。 大多数工作都集中在能量平衡的神经调节上，然而，这是一个重要但知之甚少的问题。 一个重要的因素是星形胶质细胞在能量状态调节中所起的作用，尽管它们发挥着至关重要的功能 在调节突触强度和神经活动方面。为了进一步了解肥胖的过程， 为了寻求有效的治疗方法，有必要考虑星形胶质细胞对能量稳态的影响， 确定潜在的机制。我们的长期目标是开发新的靶点， 纠正饮食诱导的肥胖症（DIO）。我们此应用程序的总体目标是确定 下丘脑星形胶质细胞来纠正DIO并确定该纠正的机制。我们的中央 有一种假说认为星形胶质细胞可以通过减少突触连接来对DIO中能量过剩做出反应并负性调节， 在小鼠弓状核（ARC）中的食欲性Agouti-related蛋白（AgRP）神经元的强度，这将是 通过提高细胞外腺苷来实现。我们的假设是根据我们最近的 研究和我们的初步数据表明，星形胶质细胞激活减少进食和沉默AgRP神经元， 腺苷A1信号传导，诱导能量消耗，并提高细胞外腺苷。的合理性 提出的研究是，一旦知道星形胶质细胞如何调节能量状态， 操纵它们来纠正或逆转肥胖，以及潜在的各种饮食失调。 为了实现我们的目标，我们组建了一个研究团队， 专业知识，包括神经胶质生物学，神经生物学和能量代谢。为了验证我们的核心假设， 从而实现我们的总体目标，我们将进行三个具体的目标：（1）确定星形胶质细胞如何 控制AgRP神经元的突触强度;（2）确定星形胶质细胞如何促进突触改变 （3）确定HFD诱导的肥胖症（DIO）治疗中的星形胶质细胞靶点。实验 这里提出的将使用多方面的方法进行检查，包括细胞类型特异性电生理学， 化学遗传学和光遗传学星形胶质细胞操作，腺苷的延时脑深部测量， 药理学和代谢测定的时间控制。腺苷增强治疗肥胖症也将 用整合的化学和遗传方法将腺苷激酶抑制剂靶向弓形虫， 星形胶质细胞使用这些尖端方法的结果将使我们前所未有地了解神经胶质细胞 控制能量状态。总之，拟议的研究代表了一个新的和实质性的偏离， 其他的研究，因为它将重点转移到开发肥胖治疗的星形胶质细胞靶点上。

Project Summary Obesity and its associated complications impose a huge burden to our society. However, the mechanisms underlying this disorder and its related pathologies remain unclear, and effective treatments are still lacking. At its core, obesity results from an imbalance between energy intake and energy expenditure. Most work has focused on neural regulation of energy balance, however, an important but poorly understood element is the role played by astrocytes in the regulation of energy states although they play crucial functions in regulating synaptic strength and neural activity. To further our understanding of the processes of obesity and to seek effective therapeutics, it is necessary to consider astrocytic influence on energy homeostasis and determine the underlying mechanisms. Our long-term goal is to enable the development of novel targets to correct diet-induced obesity (DIO). Our overall objective for this application is to determine the ability of hypothalamic astrocytes to correct DIO and determine the mechanisms of that correction. Our central hypothesis is that astrocyte can react to and negatively regulate energy surfeit in DIO by reducing the synaptic strength at orexigenic agouti-related protein (AgRP) neurons in arcuate nucleus (ARC) in mice, which will be achieved by elevating extracellular adenosine. Our hypothesis has been formulated on the basis of our recent study and our preliminary data that astrocyte activation reduces feeding and silences AgRP neurons via adenosine A1 signaling, induces energy expenditure, and elevates extracellular adenosine. The rational for the proposed research is that, once it is known how astrocytes regulate energy states, it may be feasible to manipulate them pharmacologically to correct or reverse obesity, and potentially a variety of eating disorders. To accomplish our goals, we have assembled a research team that combines a diverse range of expertise including glial biology, neurobiology, and energy metabolism. To test our central hypothesis and thereby accomplish our overall objective, we will carry out three Specific Aims: (1) Determine how astrocytes control synaptic strength at AgRP neurons; (2) Determine how astrocytes contribute to synaptic alterations during (HFD) feeding; (3) Identify astrocytic target in the treatment of HFD-induced obesity (DIO). Experiments proposed here will be examined using a multifaceted approach that includes cell type-specific electrophysiology, chemogenetic- and optogenetic astrocytic manipulation, time-lapse deep-brain measurements of adenosine, temporal control of pharmacology, and metabolic assays. Adenosine augmentation therapy in obesity will also be performed with an integrated chemical and genetic approach to target adenosine kinase inhibitor to arcuate astrocytes. Results using these cutting-edge methods will give us unprecedented access to understanding glial control of energy states. Together, the proposed research represents a new and substantial departure from other studies in that it shifts the focus to developing astrocytic targets for obesity treatment.