The Role of BDNF in VMH astrocytes influencing energy and glucose homeostasis

BDNF 在 VMH 星形胶质细胞中影响能量和葡萄糖稳态的作用

• 批准号: 9119882
• 负责人: Maribel Rios
• 金额: $ 20.63万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119882
• 关键词: Adult; Affect; Affinity Chromatography; Agreement; American; Area; Astrocytes; Behavior; Biology; Body Weight; Brain; Brain region; Brain-Derived Neurotrophic Factor; Calcium Signaling; Cardiovascular Diseases; Cells; Charge; Clinical; Collaborations; Communication; Desire for food; Development; Disease; Eating; Electrophysiology (science); Epidemic; Equilibrium; Excitatory Synapse; Exhibits; Fasting; Frequencies; Functional disorder; Gene Expression; Genes; Glucose; Glutamate Transporter; Glutamates; Health; Homeostasis; Human; Hyperglycemia; Hyperphagia; Hypothalamic structure; Insulin Resistance; Intervention; Investigation; Kinetics; Link; Measures; Mediating; Messenger RNA; Metabolic; Methods; Modeling; Molecular; Morbid Obesity; Morphology; Mus; Mutant Strains Mice; N-Methyl-D-Aspartate Receptors; Neuroglia; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Neurotrophic Tyrosine Kinase Receptor Type 2; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Play; Population; Predisposition; Receptor Signaling; Regulation; Research; Ribosomes; Risk Factors; Role; Satiation; Shapes; Signal Transduction; Synapses; Testing; Translating; United States; Variant; blood glucose regulation; density; energy balance; extracellular; feeding; global health; insight; mature animal; neural circuit; neuronal excitability; new therapeutic target; novel; protein expression; receptor; relating to nervous system; research study; satiety center; uptake

 DESCRIPTION (provided by applicant): Obesity is a risk factor for the development of type 2 diabetes, cardiovascular disease and other afflictions. Our previous studies identified a novel and critical role for brain-derived neurotrophic factor (BDNF) in central neural circuits controllig food intake and body weight. In agreement, mice with global central (BDNF2L/2LCk-cre) or selective BDNF depletion in the adult ventromedial hypothalamus (VMH) exhibit excessive feeding, obesity and metabolic disturbances. Diminished BDNF function has also been associated with hyperphagic behavior and severe obesity in humans. These findings have significant clinical implications as the BdnfVal66Met variant, which interferes with BDNF signaling, is highly prevalent among Americans. Here, we propose investigating whether BDNF regulates astrocyte structural plasticity and function to increase the excitatory drive of anorexigenic neurons in the VMH, a satiety center. Among known energy balance centers, BDNF is most abundant in the VMH, where it plays a required satiety role. Supportive evidence includes: i) robust effects of energy status on expression of BDNF and its receptor, TrkB, in the VMH, ii) the hyperphagia and obesity elicited by selectively deleting Bdnf in the VMH of adult mice iii) reduced density of excitatory synapses and decreased frequency of excitatory post synaptic currents in the VMH inBDNF2L/2LCk-cre mice. The cellular and molecular mechanisms underlying the effects of BDNF on neuronal excitability in the VMH remain to be fully elucidated. BDNF is a dynamic regulator of neuronal plasticity and alters morphology and mediates calcium signaling in astrocytes. These are significant effects as changes in glial morphology are associated with synaptic contact remodeling. Moreover, glutamate clearance by perisynaptic astrocytes is important in maintaining glutamate homeostasis and shaping synaptic currents. These effects of BDNF on astrocytes have been identified in several brain regions, but not in feeding circuits. Indeed, the role of astrocyte-neuron interactions in hypothalamic feeding circuits and the regulation of energy balance remains a vastly under studied research area. It warrants examination as dynamic changes in synaptic connectivity of hypothalamic circuits, including those involving the VMH, are thought to contribute to appetite control. As a first step t understand how astrocytes in the VMH influence feeding circuits, we propose examining the effect of energy status and BDNF on this cell population. Studies comprise examination of effects of energy status and BDNF on structural plasticity, glutamate uptake kinetics and dynamic changes in translating mRNAs in VMH astrocytes using cutting edge anatomical, electrophysiological and molecular approaches. 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.

 描述（由申请人提供）：肥胖是发生 2 型糖尿病、心血管疾病和其他疾病的危险因素。我们之前的研究发现，脑源性神经营养因子 (BDNF) 在控制食物的中枢神经回路中具有新颖且关键的作用。与成人腹内侧下丘脑 (VMH) 全局中枢 (BDNF2L/2LCk-cre) 或选择性 BDNF 耗竭的小鼠的摄入量和体重一致。 BDNF 功能减弱也与人类的暴食行为和严重肥胖有关，因为干扰 BDNF 信号传导的 BdnfVal66Met 变异在美国人中非常普遍。研究 BDNF 是否调节星形胶质细胞的结构可塑性和功能，以增加 VMH（已知的能量平衡中心）中厌食神经元的兴奋性驱动。支持性证据包括：i) 能量状态对 VMH 中 BDNF 及其受体 TrkB 表达的强烈影响，ii) 通过选择性删除 Bdnf 引起的食欲亢进和肥胖。成年小鼠的 VMH iii) BDNF2L/2LCk-cre 小鼠的 VMH 中兴奋性突触密度降低，兴奋性突触后电流频率降低。 BDNF 对 VMH 神经元兴奋性影响的细胞和分子机制仍有待充分阐明。 BDNF 是神经元可塑性的动态调节剂，可以改变星形胶质细胞的形态并介导钙信号传导，这些都是与神经胶质细胞形态变化相关的重要影响。此外，突触周围星形胶质细胞的谷氨酸清除对于维持谷氨酸稳态和形成突触电流很重要。星形胶质细胞的 BDNF 已在多个大脑区域中被发现，但在摄食回路中尚未发现。事实上，星形胶质细胞-神经元相互作用在下丘脑摄食回路和能量平衡调节中的作用仍然是一个正在广泛研究的研究领域，它值得作为动态变化进行研究。下丘脑回路的突触连接，包括涉及 VMH 的突触连接，被认为有助于食欲控制。作为了解 VMH 中的星形胶质细胞如何影响进食回路的第一步，我们建议检查研究包括使用尖端解剖学、电生理学和分子方法检查能量状态和 BDNF 对结构可塑性、谷氨酸摄取动力学以及 VMH 星形胶质细胞翻译 mRNA 的动态变化的影响。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，从而确定治疗肥胖的治疗策略的新靶标。