BDNF signaling in VMH astrocytes mediating energy and glucose balance control

VMH 星形胶质细胞中的 BDNF 信号介导能量和葡萄糖平衡控制

基本信息

批准号：
9762353
负责人：
Maribel Rios
金额：
$ 43.97万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762353
关键词：
Area Astrocytes Body Weight Brain region Brain-Derived Neurotrophic Factor Calcium Signaling Cells Communication Data Desire for food Diabetes Mellitus Disease Eating Energy Metabolism Equilibrium Excitatory Synapse Exhibits Fasting Glucose Glutamate Transporter Glutamates Growth Factor High Fat Diet Human Hyperglycemia Hyperphagia Hypothalamic structure In Vitro Insulin Resistance Investigation Kinetics Leptin Mediating Metabolic MicroRNAs Morphology Mus Mutant Strains Mice Neuronal Plasticity Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Pb clearance Play Population Population Heterogeneity Predisposition Process Regulation Reporting Research Role Satiation Signal Transduction Structure Synapses Testing Weight Gain Weight maintenance regimen adipokines blood glucose regulation density energy balance feeding follow-up global health glucose metabolism glycemic control mutant neural circuit new therapeutic target novel obesity treatment receptor reuptake uptake

项目摘要

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.

下丘脑腹内侧区（VMH）在能量和葡萄糖平衡的调节中起着至关重要的作用。它含有异质神经元群，其中大部分是谷氨酸能神经元，可以促进饱腹感并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 VMH 是介导这些作用的重要细胞底物。因此，VMH 中 BDNF 及其受体 TrkB 的表达在进食状态下被强烈诱导，并且选择性靶向该区域的 BDNF 会引发食欲亢进、肥胖和高血糖。 BDNF 除了是神经元可塑性的主要调节因子之外，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。这些影响已在多个大脑区域中被发现，但在进食回路中尚未发现。这一研究领域值得研究，因为众所周知，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，并且它们在能量和葡萄糖平衡调节中的作用正在研究中。目前的提案建立在最近完成的 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。它将检验以下假设：在正能量平衡条件下，需要增加 VMH 星形胶质细胞中的 BDNF 信号传导，以增加对调节能量和葡萄糖平衡的 VMH 神经元的兴奋性驱动，并介导食欲抑制和葡萄糖代谢。目标 1 将检查小鼠 VMH 星形胶质细胞中 TrkB.T1 的选择性已知下调的影响，因为这是该细胞群表达的唯一 TrkB 受体亚型。由于我们提出 VMH 中 BDNF 的一些影响是通过调节星形胶质细胞谷氨酸转运蛋白 GLT-1 介导的，因此目标 2 将研究删除 VMH 星形胶质细胞中的 GLT-1 对进食和禁食状态下神经元活动的影响以及能量和葡萄糖平衡的调节。最后，目标 3 将定义 VMH 星形胶质细胞中 BDNF/TrkB.T1 信号下游的机制，介导 VMH 神经元兴奋性驱动以及能量和葡萄糖稳态的变化。计划中的研究将阐明涉及 VMH 中神经胶质神经元通讯的新机制，调节喂养回路的活动和饱腹感，从而确定治疗肥胖症的治疗策略的新目标。