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A Novel AgRP Neurons to the Dorsal Raphe Circuit in Control of Energy Expenditure

中缝背侧电路中新型 AgRP 神经元控制能量消耗

基本信息

批准号：
10091316
负责人：
Qi Wu
金额：
$ 35万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-04 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10091316
关键词：
Ablation Affect Brain Brown Fat Calcium Development Direct Expenditure Dorsal Eating Electrophysiology (science)Elements Energy Metabolism Food Energy Future Genetic High Fat Diet Homeostasis Hypothalamic structure Image Infusion procedures Lateral Life Mediating Melanocortin 4 Receptor Metabolic Midbrain structure Neurons Nutritional Obese Mice Outcome Pathologic Peptide Signal Sequences Peptides Peripheral Physiological Play Process Receptor Signaling Regulation Role Serotonin Signal Pathway Signal Transduction Synapses System Temperature Testing Thermogenesis Weight Gain Weight maintenance regimen diet-induced obesity dorsal raphe nucleus effective therapy excessive weight gain feeding food consumption gamma-Aminobutyric Acid hindbrain insight metabolic rate mind control neural circuit neural network novel novel therapeutic intervention obesity treatment parabrachial nucleus response restoration

项目摘要

Project Summary: Increasing amount of evidence indicate that hypothalamic AgRP neurons control energy homeostasis by co-releasing NPY, AgRP and GABA to some specific post-synaptic targets in the brain. Recent studies suggested that activation of AgRP neurons promotes weight gain by simultaneously stimulating food intake and suppressing energy expenditure. However, it remains elusive as of how AgRP neurons organize a neural circuit to suppress thermogenesis and reduce energy expenditure in response to nutritional signals. The objective of this proposal is to gain mechanistic insights into the functional connectivity and key signaling components of a novel AgRP circuit that exerts distinct control of energy expenditure. Here, we obtained compelling results indicating that a subpopulation of AgRP neurons exert unique control of intrascapular brown adipose tissue (iBAT) thermogenesis by sending inhibitory projections to the ventral lateral part of the dorsal raphe nucleus (DRd) in the midbrain. Our central hypothesis is that a subpopulation of AgRP neurons, in response to peripheral nutritional signals, play a distinct role in suppression of energy expenditure by inhibiting MC4R- expressing 5-HT neurons in the DRd. We will test the hypothesis in the following aims: Aim 1: Determine whether a subset of AgRP neurons that project to the DRd plays a physiological role in control of energy expenditure; Aim 2: Determine whether AgRP signaling mediates thermogenesis and energy metabolism by suppression of MC4R signaling system in the DRd; Aim 3: Determine whether serotonergic signaling in the DRd plays a crucial role in the regulation of AgRP neuron- mediated energy expenditure. Our proposed studies will reveal mechanistic insights underlying the control of thermogenesis and energy metabolism by a novel neural circuit. Taken together, the potential outcome of proposed study would facilitate the elucidation of a more complete neural network and underlying signaling pathways in distinct control of energy expenditure, one of the key prerequisites to future development of effective treatment for obesity.

项目总结: