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（由适用提供）：增加证据量，表明下丘脑AGRP神经元通过将NPY，AGRP和GABA共同释放到大脑中某些特定的突触后靶标而控制能量稳态。最近的研究表明，AGRP神经元的激活通过简单地刺激食物摄入和抑制能量消耗来促进体重增加。然而，由于AGRP神经元如何组织神经元回路以抑制热生成并减少对营养信号的能量消耗，因此仍然难以捉摸。该提案的目的是获得对新型AGRP电路的功能连通性和关键信号成分的机械见解，该电路对能量消耗施加了明显的控制。在这里，我们获得了引人注目的结果，表明AGRP神经元的亚群通过向中脑背侧raphe核us（DRD）的腹侧侧面发送抑制性投影来对棕色脂肪组织（IBAT）的热发生独特控制。我们的核心假设是，AGRP神经元的亚群，响应周围营养信号，通过抑制DRD中表达MC4R的5-HT神经元的能量消耗中起着独特的作用。我们将在以下目的中检验假设：目标1：确定投射到DRD的AGRP神经元的子集是否在控制能量消耗中起身体作用； AIM 2：确定AGRP信号是否通过抑制DRD中的MC4R信号系统介导生热和能量代谢； AIM 3：确定DRD中的血清能信号在调节AGRP神经介导的能量消耗中是否起着至关重要的作用。我们提出的研究将揭示通过新型神经元回路控制热和能量代谢的基础的机械见解。综上所述，拟议研究的潜在结果将支持阐明更完整的神经元网络和基础信号通路，以独特的能量消耗控制，这是对物体性有效治疗的未来发展的关键先决条件之一。