权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Astrocytic regulation of energy balance on high-fat diet

星形胶质细胞对高脂饮食能量平衡的调节

基本信息

批准号：
10734911
负责人：
BAOJI XU
金额：
$ 75.47万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-09 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734911
关键词：
Ablation Age Astrocytes Axon Binding Brain Brain region Brain-Derived Neurotrophic Factor Ca(2+)-Transporting ATPase Cell membrane Cells Development Dimerization Energy Intake Energy Metabolism Fat-Restricted Diet Gene Deletion Glutamates Growth High Fat Diet Homeostasis Human Hyperactivity Hyperphagia Hypothalamic structure ITPR1 gene Impairment Injections Inositol Knock-out Knockout Mice Lead Length Measures Mediating Minor Morbid Obesity Morphology Mus Mutation NTRK2 gene Nerve Degeneration Neurons Neurotransmitters Neurotrophic Tyrosine Kinase Receptor Type 2 Nutritional Nutritional Support Obesity Phosphotransferases Play Process Protein Isoforms RNA Splicing Reducing diet Regulation Reporting Research Project Grants Resistance Role Signal Pathway Signal Transduction Site Slice Structure Structure of nucleus infundibularis hypothalami Synapses Synaptic Cleft Synaptic Transmission Testing Therapeutic Intervention Tropomyosin Tyrosine Kinase Domain Variant antagonist astrogliosis attenuation conditional knockout density diet-induced obesity energy balance excitotoxicity experimental study feeding knock-down neuron development neuronal survival neurotoxic neurotransmission novel obesity prevention prevent receptor response rho GTP-Binding Proteins transmission process tripolyphosphate uptake

项目摘要

Summary Brain-derived neurotrophic factor (BDNF) binds to full-length tropomyosin receptor kinase (TrkB.FL), inducing its dimerization and activation. This activates many signaling cascades that cooperatively promote neuronal survival and regulate neuronal development and synaptic transmission in many brain regions. This signaling pathway is also critical for the control of energy balance, as mutations in the TrkB.FL kinase domain or BDNF lead to hyperphagia and severe obesity in mice and humans. In addition to TrkB.FL, the Ntrk2 gene produces two truncated receptors, a predominant TrkB.T1 and a minor TrkB.T2 (we use TrkB.T to refer both isoforms). TrkB.T has a short intracellular sequence and lacks the tyrosine kinase domain. Neurons mainly express TrkB.FL, whereas astrocytes only express TrkB.T. While binding of BDNF to TrkB.T1 induces Ca2+ signals and activates Rho GTPase in cultured astrocytes, it remains unclear if astrocytic TrkB.T plays a role in the control of energy balance. We generated astrocyte specific Ntrk2 conditional knockout (aNtrk2 cKO) mice where Ntrk2 deletion starts at 5 weeks of age and abolishes TrkB.T expression in astrocytes. We found that the Ntrk2 deletion in mature astrocytes blocked astrocytic reactivity in the arcuate nucleus of the hypothalamus (ARH) and gave mice total resistance to diet-induced obesity (DIO) by reducing energy intake and increasing energy expenditure. In addition to nutritional and trophic support to neurons, astrocytes contact synapses through their processes to regulate synaptic transmission by taking up neurotransmitters from the synaptic cleft and releasing gliotransmitters into the synaptic cleft. Thus, we hypothesize that TrkB.T-mediated Ca2+ signals promote astrocytic reactivity in response to high-fat diet (HFD) feeding, which in turn disrupts astrocytic support to neurons and astrocytic regulation of synapses and shifts energy homeostasis to energy surplus. Our studies will focus on astrocytes, AgRP/NPY neurons, and POMC neurons in the ARH. We propose to examine the impact of Ntrk2 gene deletion on astrocytes in the ARH (Aim 1), to determine the impact of astrocytic Ntrk2 deletion on neurons and synaptic transmission (Aim 2), to identify the site where astrocytic TrkB.T ablation blocks diet-induced obesity (Aim 3), and to determine if attenuating astrocytic Ca2+ signals can prevent obesity in HFD-fed mice (Aim 4). In conclusion, this research project will test several novel concepts, including a crucial role for TrkB.T- mediated Ca2+ signals in induction of astrocytic reactivity, an active role for TrkB.T in the regulation of energy balance, and altered astrocytic regulation of synaptic transmission in HFD-fed mice. Our studies will likely show that attenuating TrkB.T-mediated Ca2+ signals in astrocytes can be a novel and effective strategy for therapeutic interventions of DIO, the most common form of obesity in humans.

总结