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

项目总结： 越来越多的证据表明，下丘脑AgRP神经元控制能量平衡 通过将NPY、AgRP和GABA共同释放到大脑中特定的突触后靶点。近期 研究表明，激活AgRP神经元通过同时促进体重增加 刺激食物摄入，抑制能量消耗。然而，它仍然难以捉摸，因为如何 AgRP神经元组织神经回路以抑制产热和减少能量消耗 对营养信号的反应。这项建议的目标是获得对 一种新型AgRP电路的功能连通性和关键信号组件 控制能源消耗。在这里，我们获得了令人信服的结果，表明 AgRP神经元通过以下方式独特地控制肩关节内棕色脂肪组织(IBAT)的产热 向中缝背核腹外侧部投射抑制性投射 中脑。我们的中心假设是AgRP神经元的一个亚群，对外周的反应 营养信号，通过抑制MC4R，在抑制能量消耗方面发挥着明显的作用。 5-羟色胺神经元在延髓背核的表达。我们将在以下目标中检验这一假设：目标1： 确定投射到DRD的AgRP神经元的子集是否在 能量消耗的控制；目标2：确定AgRP信号是否介导产热 和通过抑制DRD中的MC4R信号系统的能量代谢；目标3：确定 DRD中的5-羟色胺能信号是否在AgRP神经元的调节中起关键作用 调节能量消耗。我们提议的研究将揭示 通过一种新的神经回路控制产热和能量代谢。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 而潜在的信号通路在不同的能量消耗控制中是关键之一 未来开发有效治疗肥胖症的先决条件。

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.