BDNF signaling in VMH astrocytes mediating energy and glucose balance control

下丘脑腹内侧（VMH）在调节能量和葡萄糖平衡中起着至关重要的作用。它包含一个异质的神经元群，主要是谷氨酸能，促进饱腹感，调节能量消耗和血糖控制。我们之前的研究揭示了脑源性神经营养因子（BDNF）在控制食物摄入的中枢神经回路中的关键作用，并确定了VMH是介导这些作用的重要细胞底物。因此，在进食状态下，BDNF及其受体TrkB在VMH中的表达被强烈诱导，BDNF在该区域的选择性靶向会引发贪食、肥胖和高血糖。除了作为神经元可塑性的主要调节因子外，BDNF还是一种多功能生长因子，据报道对星形胶质细胞形态和钙信号传导有影响。这些影响已经在大脑的几个区域被发现，但在进食回路中没有。星形胶质细胞通过胶质递质释放、谷氨酸清除和突触重塑在调节神经元活动中发挥积极作用，其在能量和葡萄糖平衡调节中的作用已得到充分研究，因此这一研究领域值得进一步研究。目前的建议建立在最近完成的R21项目的基础上，该项目揭示了能量状态和BDNF调节VMH中的星形胶质细胞功能，包括结构可塑性和谷氨酸摄取动力学。该研究将验证在正能量平衡条件下，VMH星形胶质细胞中BDNF信号的增加是增加对调节能量和葡萄糖平衡的VMH神经元的兴奋驱动并介导食欲抑制和葡萄糖代谢的必要条件。目的1将研究TrkB选择性下调的影响。T1在小鼠VMH星形胶质细胞中表达，因为这是该细胞群中唯一表达的TrkB受体亚型。由于我们提出BDNF在VMH中的一些作用是通过调节星形胶质细胞谷氨酸转运蛋白GLT-1介导的，Aim 2将研究在VMH星形胶质细胞中删除GLT-1对喂养和禁食状态下神经元活性以及能量和葡萄糖平衡调节的影响。最后，Aim 3将定义BDNF/TrkB下游的机制。VMH星形胶质细胞T1信号介导VMH神经元兴奋性驱动及能量和葡萄糖稳态的变化。计划中的研究将阐明下丘脑神经胶质-神经元通讯的新机制，从而调节进食回路和饱腹感的活动，从而确定治疗肥胖的新靶点。

The ventromedial hypothalamus (VMH) plays paramount roles in the regulation of energy and glucose balance. It contains a heterogeneous population of neurons, mostly glutamatergic that promote satiety and regulate energy expenditure and glycemic control. Our previous studies revealed a critical role for brain-derived neurotrophic factor (BDNF) in central neural circuits controlling food intake and identified the VMH as an important cellular substrate mediating these actions. Accordingly, expression of BDNF and its receptor TrkB in VMH is robustly induced in the fed state and selective targeting of BDNF in this region triggers hyperphagia, obesity and hyperglycemia. In addition to being a chief regulator of neuronal plasticity, BDNF is a multifunctional growth factor with reported effects on astrocyte morphology and calcium signaling. These effects have been identified in several brain regions, but not in feeding circuits. This research area warrants examination as it is well established that astrocytes play an active role in regulating neuronal activity via gliotransmitter release, glutamate clearance and synapse remodeling and their role in energy and glucose balance regulation has been under studied. The current proposal builds on a recently completed R21 project revealing that energy status and BDNF regulate astrocyte function in the VMH, including structural plasticity and glutamate uptake kinetics. It will test the hypothesis that increased BDNF signaling in VMH astrocytes during conditions of positive energy balance is required to increase the excitatory drive onto energy and glucose balance-regulating VMH neurons and mediate appetite suppression and glucose metabolism. Aim 1 will examine the effects of selective known down of TrkB.T1 in VMH astrocytes in mice, as this is the only TrkB receptor subtype expressed by that cell population. As we propose that some of the effects of BDNF in the VMH are mediated through regulation of the astrocytic glutamate transporter, GLT-1, Aim 2 will investigate the consequences of deleting GLT-1 in VMH astrocytes on neuronal activity in the fed and fasted states and in the regulation of energy and glucose balance. Finally, Aim 3 will define mechanisms downstream of BDNF/TrkB.T1 signaling in VMH astrocytes mediating changes in the excitatory drive of VMH neurons and energy and glucose homeostasis. The planned studies will elucidate novel mechanisms involving glial-neuron communication in the VMH that regulate activity of feeding circuits and satiety and thereby identify new targets for therapeutic strategies to treat obesity.