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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.

项目总结