Neural pathways for obesity development by AgRP neurons

AgRP 神经元导致肥胖发展的神经通路

基本信息

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
项目类别：
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

项目摘要

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.

项目概要由于副作用，治疗肥胖症的治疗药物的开发尚未成功并且功效有限。我的长期研究目标是描绘负责体重的神经通路体内平衡，并为有效和特异性的肥胖治疗提供框架。研究领域近几十年来，我们发现下丘脑中的弓形神经元表达刺鼠相关蛋白（AgRP）作为喂养的关键节点。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瘦素受体的缺失会导致饮食中的严重肥胖，其程度与瘦素相当不足。 AgRP 神经元已知会释放 GABA、NPY 和 AgRP，并独立且并行地发送信号对几个关键大脑部位的预测。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，如何神经递质和个体 AgRP 神经元投射介导慢性肥胖症造成的肥胖 AgRP 神经元的激活尚不清楚。此外，单个 AgRP 神经元投射如何介导瘦素对肥胖的作用尚不清楚为了解决这些知识差距，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（目标 2）及其 LepR 表达（目标 3）在介导中的作用 AgRP 神经元慢性激活引起的肥胖症。先进的病毒追踪和交叉小鼠遗传学将用于实现 AgRP 神经元的投射特异性操作实现强有力的调查。这个提议是基于我们之前建立的巨大肥胖小鼠 AgRP 神经元慢性激活或 AgRP 神经元中 LepR 缺失的模型，并利用以下组合诱导删除和追踪，以检查个体发射器和投射的相对重要性肥胖的发展。该结果将填补AgRP神经元潜在神经回路机制的空白肥胖发展，并将建立阶段来确定关键的下游介质和神经元介导瘦素和 AgRP 神经元在肥胖发展中的作用，代表着理解大脑的重要一步体重调节机制。