Neural pathways for obesity development by AgRP neurons

AgRP 神经元导致肥胖发展的神经通路

• 批准号: 10681993
• 负责人: Qingchun Tong
• 金额: $ 44.73万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-19 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681993
• 关键词: ART protein; Ablation; Acute; Address; Adult; Animal Model; Area; Bacteria; Body Weight; Brain; Chronic; Cues; Development; Diet; Energy Metabolism; Exhibits; Feeding behaviors; Foundations; Functional disorder; Goals; Homeostasis; Hypothalamic structure; Individual; Investigation; Knowledge; Lateral Hypothalamic Area; Leptin; Leptin deficiency; Mediating; Mediator; Modeling; Mus; Neonatal; Neural Pathways; Neurons; Neurotransmitters; Nutritive Value; Obese Mice; Obesity; Obesity Epidemic; Pathway interactions; Pharmaceutical Preparations; Play; Pro-Opiomelanocortin; Regulation; Research; Rodent; Role; Site; Sodium Channel; Structure of terminal stria nuclei of preoptic region; Subgroup; Thalamic structure; Therapeutic; Viral; design; effective therapy; feeding; gamma-Aminobutyric Acid; hindbrain; leptin receptor; midbrain central gray substance; mouse genetics; mouse model; neonate; neuropeptide Y; neurotransmitter release; obesity development; overexpression; parabrachial nucleus; pharmacologic; receptor expression; segregation; side effect; therapeutic development

Project Summary The development of therapeutic drugs to cure obesity has not been successful due to unwanted side effects and limited efficacy. My long-term research goal is to delineate neural pathways responsible for body weight homeostasis, and provide a framework for effective and specific therapeutics against obesity. Research in the last decades has identified arcuate neurons in the hypothalamus expressing agouti-related protein (AgRP) as a key node in feeding. Recently, we and others demonstrate that chronic activation of AgRP neurons or adult deletion of leptin receptors in these neurons leads to massive obesity on chow diet that is comparable to leptin deficiency. AgRP neurons are known to release GABA, NPY and AgRP and send independent and parallel projections to several key brain sites. Importantly, the expression of leptin receptor has been suggested to be more prominent in those AgRP neurons that project to extra-hypothalamic areas. However, how the neurotransmitters and the individual AgRP neuron projections mediate the obesity produced by chronic activation of AgRP neurons are unknown. Additionally, how the individual AgRP neuron projections mediates leptin action on obesity is also unknown To address these knowledge gaps, we aim to examine the role of AgRP individual neurotransmitters (Aim 1), projection-specific subpopulations of AgRP neurons (Aim 2) and their LepR expression (Aim 3) in mediating the obesity development produced by chronic AgRP neuron activation. Advanced viral tracing and intersectional mouse genetics will be used to achieve projection-specific manipulations in AgRP neurons to achieve robust investigation. This proposal is based on our previously established massive obese mouse models with chronic AgRP neuron activation or LepR deletion in AgRP neurons, and utilizes a combination of inducible deletion and tracing to ex-amine the relative importance of individual transmitters and projections in obesity development. The results will fill the gap in the underlying neurocircuit mechanism for AgRP neurons on obesity development and will set up stages to identify key downstream mediators and neurons mediating leptin and AgRP neurons in obesity development, representing a significant step in understanding brain mechanisms in body weight regulation.

项目摘要 由于不必要的副作用，治疗药物的开发尚未成功 和有限的功效。我的长期研究目标是描述负责体重的神经途径 体内平衡，并为抗肥胖症提供了有效和特定的治疗剂的框架。研究 最近的几十年已经确定了表达Agouti相关蛋白（AGRP）的下丘脑中的神经元 喂食中的关键节点。最近，我们和其他人证明了AGRP神经元或成人的长期激活 这些神经元中瘦素受体的缺失会导致食物上的大量肥胖，与瘦素相当 不足。已知AGRP神经元可以释放GABA，NPY和AGRP，并独立和平行发送 投影到几个关键的大脑站点。重要的是，已经提出瘦素受体的表达为 在那些投射到高层丘脑区域的AGRP神经元中更为突出。但是，如何 神经递质和个体AGRP神经元投影介导慢性产生的肥胖症 AGRP神经元的激活未知。此外，单个AGRP神经元投影如何介导 瘦素对肥胖的作用也是未知的 为了解决这些知识差距，我们旨在研究AGRP个体神经递质的作用（AIM 1）， AGRP神经元（AIM 2）及其LEPR表达（AIM 3）的投影特异性亚群（AIM 3） 慢性AGRP神经元激活产生的肥胖发育。高级病毒跟踪和 小鼠遗传学将用于实现AGRP神经元中的投影特异性操作 实现强大的调查。该提议基于我们先前确定的大量肥胖老鼠 AGRP神经元中具有慢性AGRP神经元激活或LEPR缺失的模型，并利用 可诱导的删除和追踪到前胺，单个发射器和预测的相对重要性 肥胖发展。结果将填补AGRP神经元的基本神经回路机制的空白 关于肥胖的发展，并将设立阶段以识别下游介质和神经元的介导 肥胖发育中的瘦素和AGRP神经元，代表了理解大脑的重要一步 体重调节机制。