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

• 批准号: 9238333
• 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
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-04 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238333
• 关键词: Ablation; Affect; Biological Neural Networks; Brain; Brown Fat; Calcium; Development; Diet; 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; dorsal raphe nucleus; effective therapy; feeding; food consumption; gamma-Aminobutyric Acid; hindbrain; insight; metabolic rate; mind control; neural circuit; novel; novel therapeutics; obesity treatment; parabrachial nucleus; response; restoration

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.

项目概要： 越来越多的证据表明下丘脑AgRP神经元控制能量稳态 通过将NPY、AgRP和GABA共同释放到脑中的某些特定突触后靶点。最近 研究表明，AgRP神经元的激活通过同时促进体重增加， 刺激食物摄入并抑制能量消耗。然而，它仍然难以捉摸， AgRP神经元组织神经回路以抑制产热并减少能量消耗， 对营养信号的反应。该提案的目的是获得对 一种新型AgRP电路的功能连接和关键信号组件， 控制能源消耗。在这里，我们得到了令人信服的结果，表明一个亚群的 AgRP神经元发挥独特的控制肩胛内棕色脂肪组织（iBAT）产热， 向中缝背核腹外侧部发出抑制性投射 中脑我们的中心假设是，AgRP神经元的亚群，在响应外周血中的 营养信号，通过抑制MC 4 R在抑制能量消耗中发挥独特的作用， 5-HT阳性神经元。我们将在以下目标中检验假设：目标1： 确定投射到DRd的AgRP神经元的子集是否在以下方面发挥生理作用： 目的2：确定AgRP信号传导是否介导产热 通过抑制DRd中的MC 4 R信号传导系统来调节细胞的代谢和能量代谢;目的3：确定 DRd中的AgRP能信号传导是否在AgRP神经元的调节中起关键作用， 介导的能量消耗。我们提出的研究将揭示潜在的机械见解， 通过一种新的神经回路控制产热和能量代谢。总的来说， 拟议研究的潜在结果将有助于阐明一个更完整的神经网络 和潜在的信号通路在不同的控制能量消耗，其中一个关键 这是未来开发有效治疗肥胖症的先决条件。