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: 9220873
• 负责人: Qi Wu
• 金额: $ 10.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220873
• 关键词: Affect; Biological Assay; Biological Neural Networks; Brain; Brown Fat; Development; Diet; Dorsal; Eating; Elements; Energy Metabolism; Expenditure; Food; Future; Health; High Fat Diet; Homeostasis; Hypothalamic structure; Image; Lateral; Life; Mediating; Melanocortin 4 Receptor; Metabolic; Metabolism; Microinjections; Midbrain structure; Mus; Neurons; Nutritional; Obesity; Outcome; 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; gamma-Aminobutyric Acid; hindbrain; insight; metabolic rate; mind control; neural circuit; novel; novel therapeutics; parabrachial nucleus; response

 DESCRIPTION (provided by applicant): 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.

 描述（由申请人提供）：越来越多的证据表明，下丘脑AgRP神经元通过共同释放NPY、AgRP和GABA到大脑中的某些特定突触后靶点来控制能量稳态。最近的研究表明，AgRP神经元的激活通过同时刺激食物摄入和抑制能量消耗来促进体重增加。然而，AgRP神经元如何组织神经回路以抑制产热并减少能量消耗以响应营养信号仍然是难以捉摸的。该提案的目的是获得一种新型AgRP电路的功能连接和关键信号组件的机械见解，该电路对能量消耗进行独特的控制。在这里，我们得到了令人信服的结果表明，AgRP神经元的亚群施加独特的控制肩胛骨内棕色脂肪组织（iBAT）产热发送抑制性预测中缝背核（DRd）的腹外侧部分在中脑。我们的中心假设是，AgRP神经元的一个亚群，在响应外周营养信号，发挥了独特的作用，通过抑制MC 4 R表达的5-HT神经元在DRd的能量消耗的抑制。我们将在以下目的中检验该假设：目的1：确定投射到DRd的AgRP神经元的子集是否在控制能量消耗中起生理作用;目的2：确定AgRP信号传导是否通过抑制DRd中的MC 4 R信号传导系统来介导产热和能量代谢;目的3：确定DRd中的AgRP能信号传导是否在AgRP神经元介导的能量消耗的调节中起关键作用。我们提出的研究将揭示一种新的神经回路控制产热和能量代谢的机制。总而言之，拟议研究的潜在结果将有助于阐明更完整的神经网络和潜在的信号通路，以明确控制能量消耗，这是未来开发有效治疗肥胖的关键先决条件之一。