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 治疗肥胖症的治疗药物的开发由于不希望的副作用而没有成功 和有限的功效。我的长期研究目标是描绘出负责体重的神经通路 体内平衡，并提供了针对肥胖症有效和特异性治疗的框架。的研究 最近几十年来，已经确定下丘脑中表达刺鼠相关蛋白（AgRP）的弓状神经元是一种神经元。 关键节点喂养。最近，我们和其他人证明，AgRP神经元或成人的慢性激活， 这些神经元中的瘦素受体的缺失导致与瘦素相当的食物饮食的大量肥胖 缺陷已知AgRP神经元释放GABA、NPY和AgRP，并独立且平行地发送 投射到大脑的几个关键部位重要的是，瘦素受体的表达被认为是 在投射到下丘脑外区域的AgRP神经元中更为突出。然而， 神经递质和单个AgRP神经元投射介导慢性肥胖产生的肥胖。 AgRP神经元的激活是未知的。此外，单个AgRP神经元投射如何介导 瘦素对肥胖作用也是未知的 为了解决这些知识缺口，我们的目标是研究AgRP个体神经递质的作用（目标1）， AgRP神经元的投射特异性亚群（Aim 2）及其LepR表达（Aim 3）介导 慢性AgRP神经元激活引起的肥胖发展。先进的病毒追踪和 交叉小鼠遗传学将用于实现AgRP神经元中的投射特异性操作， 实现强有力的调查。这个建议是基于我们先前建立的巨大肥胖小鼠 用慢性AgRP神经元激活或AgRP神经元中的LepR缺失建立模型，并利用 可诱导缺失和追踪到前胺的相对重要性，个别递质和预测， 肥胖发展该结果将填补AgRP神经元神经回路机制的差距 并将建立阶段，以确定关键的下游介质和神经元介导的肥胖发展， 肥胖发展中的瘦素和AgRP神经元，代表了理解大脑的重要一步 体重调节机制。