The role of vagal afferent neurons in regulating feeding behavior

迷走神经长期以来一直被认为在调节食物摄入方面发挥作用。迷走神经传入 神经通路感知肠道对营养提示的反应而释放的激素，并将这些信号传递给 脑干我们最近已经证明，迷走神经传入神经元（货车）可以整合这些信号， 改变在感觉和信号传导中重要的受体和神经肽递质的表达， 摄食行为在肥胖症中，货车中关键受体对其配体的敏感性降低，导致 这些神经元的神经化学表型的变化。不幸的是， 该领域不允许在体内操作这些神经元以确定这些蛋白质的功能作用 关于进食行为。这项提议的首要目标是确定迷走神经在以下方面的作用： 调节摄食行为，特别关注了解迷走神经传入信号的失调 导致饮食诱导的肥胖症中的食欲过盛和体重增加。为了实现这一目标，我们 建议1）确定可卡因和安非他明调节的神经肽递质的作用 转录本（CART）和黑色素浓缩激素（MCH）从货车释放到脑干中， 正常生理条件下摄食行为的调节及其在饮食进展中的作用 诱导肥胖，2）货车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物早期生长反应1（EGR-1）的干预研究 以防止饮食引起的肥胖症的发生。这项建议的一个关键组成部分是制定一个 针对货车表达的靶蛋白的体内RNAi新方法。本研究的预期结果 本发明提出了一种新的体内RNAi方法，以靶向货车表达的蛋白质， 证明这项技术可以作为肥胖症的治疗工具，也可以作为研究工具， 阐明货车的作用。此外，成功完成将表明货车在以下方面的重要作用： 发育性摄食过多和体重增加;从而鉴定了新的特异性分子靶点， 治疗肥胖症。

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.