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

• 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
• 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

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.

下丘脑腹内侧核(VMH)在能量和糖平衡的调节中起着重要作用。它包含一个不同种类的神经元群体，主要是谷氨酸能神经元，它们促进饱腹感，调节能量消耗和血糖控制。我们以前的研究揭示了脑源性神经营养因子(BDNF)在中枢神经回路控制食物摄取中的关键作用，并发现VMH是介导这些作用的重要细胞底物。因此，在FED状态下，VMH中BDNF及其受体TrkB的表达被强烈地诱导，在该区域选择性靶向BDNF会引发高吞噬、肥胖和高血糖。除了是神经元可塑性的主要调节因子外，BDNF还是一种多功能的生长因子，据报道对星形胶质细胞的形态和钙信号有影响。这些影响已经在大脑的几个区域被发现，但在进食回路中却没有。这一研究领域值得研究，因为星形胶质细胞通过释放胶质递质、清除谷氨酸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一直被研究得很少。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中星形胶质细胞的功能，包括结构可塑性和谷氨酸摄取动力学。它将验证一种假设，即在能量正平衡的条件下，VMH星形胶质细胞中BDNF信号的增加是为了增加对能量和葡萄糖平衡调节的VMH神经元的兴奋性驱动，并介导食欲抑制和葡萄糖代谢。目的1将研究选择性下调TrkB.T1对小鼠VMH星形胶质细胞的影响，因为这是该细胞群表达的唯一TrkB受体亚型。由于我们提出脑源性神经营养因子在VMH中的一些作用是通过调节星形胶质细胞谷氨酸转运体GLT-1来实现的，因此AIM 2将研究在VMH星形胶质细胞中缺失GLT-1对摄食和禁食状态下神经元活动的影响，以及在能量和葡萄糖平衡调节中的作用。最后，Aim 3将确定VMH星形胶质细胞中BDNF/TrkB.T1信号的下游机制，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中神经胶质细胞通讯的新机制，这些机制调节喂养回路和饱腹感的活动，从而确定治疗肥胖症的新靶点。