The role of vagal afferent neurons in regulating feeding behavior

长期以来，迷走神经一直被认为在食物摄入量的调节中起作用。迷走神经传入 PATH感知肠道释放的激素，以响应营养提示，并将这些信号传递给 脑干。我们最近证实，迷走神经传入神经元(VAN)可以整合这些信号并 改变在感觉和信号传递中重要的受体和神经肽递质的表达，以修改 进食行为。在肥胖患者中，关键受体对其配体的敏感性在VAN中降低，导致 这些神经元的神经化学表型的变化。不幸的是，目前在 该领域不允许在活体内操纵这些神经元来确定这些蛋白质的功能作用 关于觅食行为。这项提议的首要目标将是确定迷走神经在 调节摄食行为，特别关注了解迷走神经传入信号的异常调节 在饮食诱导的肥胖中导致过度吞噬和体重增加。为了实现这一目标，我们 建议1)确定可卡因和苯丙胺调节的神经肽递质的作用 转录本(CART)和黑色素浓缩激素(MCH)从VAN释放到脑干中 正常生理条件下摄食行为的调节及其在进食过程中的作用 诱导肥胖，2)VAN中瘦素抵抗对肥胖进展的影响，以及3)使用 针对MCH和瘦素受体下游效应因子早期生长反应1的干预研究 预防饮食性肥胖的发生。这项提案的一个关键组成部分涉及开发一种 VAN表达的靶蛋白的体内RNAi新方法。这项研究的预期结果 建议开发一种新的体内RNAi方法来处理VAN表达的靶蛋白，并 证明这项技术可以作为肥胖症的治疗工具和研究工具来应用 阐明VAN的作用。此外，成功竣工将证明VAN在 出现吞噬过度和体重增加；从而识别新的特定分子靶点 肥胖的治疗。

The vagus nerve has long been known to play a role in the regulation of food intake. The vagal afferent pathway senses hormones released from the gut in response to nutritional cues and relays these signals to the brain stem. We have recently demonstrated that vagal afferent neurons (VAN) can integrate these signals and alter expression of receptors and neuropeptide transmitters important in sensing and signalling, to modify feeding behavior. In obesity, the sensitivity of key receptors to their ligands are reduced in VAN, resulting in changes in the neurochemical phenotype of these neurons. Unfortunately the techniques currently available in the field do not allow manipulations of these neurons in vivo to determine the functional role of these proteins on feeding behavior. The overarching goal of this proposal will be to determine the role of the vagus nerve in regulating feeding behaviour with specific focus on understanding how dysregulation of vagal afferent signaling leads to the development of hyperphagia and weight gain in diet induced obesity. To achieve this goal we propose to 1) determine the role of the neuropeptide transmitters cocaine and amphetamine regulated transcript (CART), and melanin concentrating hormone (MCH) released from VAN into the brain stem in the regulation of feeding behavior under normal physiological conditions and their role in the progression of diet induced obesity, 2) the effect of leptin resistance in VAN on the progression of obesity, and 3) to use an intervention study targeting MCH and the leptin receptor downstream effector early growth response 1 (EGR-1) to prevent the onset of diet induced obesity. A key component of this proposal involves the development of a novel in vivo RNAi approach to target proteins expressed by VAN. The expected outcomes of this research proposal are to develop a novel in vivo RNAi approach to target proteins expressed by VAN and to demonstrate that this technique could be applied as a therapeutic tool in obesity as well as a research tool to elucidate the role of VAN. In addition, successful completion would demonstrate an important role for VAN in the development hyperphagia and weight gain; thereby identifying novel specific molecular targets for the treatment of obesity.