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.

项目摘要： 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释放，AGRP和GABA与大脑中某些特定的突触后靶标。最近的 研究表明，AGRP神经元的激活同时促进体重增加 刺激食物摄入和抑制能量消耗。但是，这仍然难以捉摸 AGRP神经元组织神经回路以抑制生热并减少能量消耗 对营养信号的反应。该提议的目的是获得对 新型AGRP电路的功能连通性和关键信号传导组件，该电路发挥不同的作用 能源消耗的控制。在这里，我们获得了令人信服的结果，表明 AGRP神经元通过对棕色脂肪组织（IBAT）热生成的独特控制 将抑制性投影发送到背侧raphe核（DRD）的腹侧侧面 中脑。我们的中心假设是响应周围的AGRP神经元的亚群 营养信号，通过抑制MC4R-- 在DRD中表达5-HT神经元。我们将在以下目的中检验该假设：目标1： 确定向DRD投射的AGRP神经元的子集是否在 控制能量消耗； AIM 2：确定AGRP信号是否介导了热发生 通过抑制DRD中MC4R信号系统的能量代谢；目标3：确定 DRD中的血清素能信号是否在调节AGRP神经元的调节中起着至关重要的作用 介导的能量消耗。我们提出的研究将揭示机械洞察力 通过新的神经回路控制热生成和能量代谢。总的来说， 拟议研究的潜在结果将有助于阐明更完整的神经网络 和基础信号通路以独特的能量消耗控制，这是关键之一 未来开发有效治疗肥胖症的先决条件。