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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

基本信息

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
项目类别：
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

项目摘要

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.