High fat diet induced remodeling of preproglucagon neuronal control of feeding behavior

项目摘要 获得高热量、可口的食物促进了肥胖症的流行。虽然许多研究都集中在 在研究已经肥胖的状态下，分子机制是如何失调的方面， 关于暴露于致肥胖饮食后发生的早期事件，以及这可能最终导致 肥胖症的发展我们小组和其他人进行的研究评估了 在啮齿动物中获得高脂肪饮食（HFD）显示出进食模式的时间依赖性改变。具体地说， 在暴露于HFD后，啮齿动物经历短暂的摄食过度期（24-48小时），随后是 恢复正常饮食（72小时），然后逐渐恢复过量的热量消耗 在几周内。阐明了调节不同喂养模式的机制， 暴露于HFD的早期阶段和肥胖症之前可以确定重要的分子靶点， 用于预防性或干预性治疗肥胖症。本申请旨在 评估HFD暴露改变迷走神经传入神经元（VAN）之间相互作用的程度 和前脑前胰高血糖素原（PPG）神经元在摄食行为控制中的作用。VAN扮演着重要的角色 在将饱腹感和其他食物摄入相关信号从外周传递到中枢神经系统中， （CNS）。孤束核（NTS）中的PPG神经元是胰高血糖素样肽-1（GLP-1）的主要来源 GLP-1是一种饱腹感因子，通过对GLP-1受体的作用减少热量摄入 （GLP 1 R）在CNS中。VAN直接支配NTS PPG神经元的事实表明，这是一个关键， 相互作用调节摄食行为。然而，HFD对VAN-PPG神经元相互作用的影响和 对控制食物摄入的后续影响尚未确定。实验1旨在评估 高脂饮食给药对后脑中VAN-PPG相互作用的时间依赖性影响，并测试 假设VAN-PPG神经元沉积的减少与 HFD。实验2提出具体表征PPG神经元对进食模式的影响 HFD给药后，通过选择性消融/抑制NTS PPG神经元。我们假设 NTS PPG神经元的损失/抑制将加剧与HFD给药相关的摄食过度 增加恢复正常进食的时间本研究申请中提出的实验将 使我能够获得宝贵的研究培训和经验，使用最先进的实验技术 并将加强我作为一名独立研究科学家的能力。

PROJECT SUMMARY Access to calorie dense, palatable foods has promoted an obesity epidemic. While much research has focused on investigating how molecular mechanisms may be dysregulated in the already obese state, little is known about the early events that occur upon exposure to obesogenic diets and how this may ultimately contribute to the progression towards obesity. Studies conducted by our group and others evaluating the consequences of access to high-fat diet (HFD) in rodents has shown time dependent alterations in feeding patterns. Specifically, following exposure to a HFD rodents experience a transient period of hyperphagia (24-48 hours) followed by a return to normophagia (by 72 hours) and then a subsequent gradual return to excessive caloric consumption over a period of weeks. Elucidating the mechanisms that regulate the different feeding patterns evident during the early stages of exposure to a HFD and prior to obesity can identify important molecular targets that may be leveraged for either preventative or interventional therapeutics against obesity. This application aims to assess the extent to which HFD exposure modifies interactions between vagal afferent neurons (VANs) and hindbrain preproglucagon (PPG) neurons in the control of feeding behavior. VANs play a critical role in relaying satiety and other food-intake related signaling from the periphery to the central nervous system (CNS). PPG-neurons in the nucleus tractus solitarius (NTS) are the main source of Glucagon-like peptide-1 (GLP-1) in the CNS, and GLP-1 is a satiety factor that reduces caloric intake via actions on a GLP1-receptor (GLP1R) in the CNS. The fact that VANs directly innervate NTS PPG neurons suggests that this is a key interaction regulating feeding behavior. However, the influence of HFD on VAN-PPG neuron interactions and subsequent effects on the control of food intake have not been established. Experiment 1 aims to evaluate the time dependent effects of high-fat diet administration on VAN-PPG interactions in the hindbrain and tests the hypothesis that decreases in VAN-PPG neuronal apposition are associated with hyperphagic responses to HFD. Experiment 2 proposes to specifically characterize the influence of PPG neurons on feeding patterns following HFD administration through selective ablation/inhibition of NTS PPG neurons. We hypothesize that the loss/inhibition of NTS PPG neurons will exacerbate the hyperphagia associated with HFD administration and increase the time to return to normophagia. The experiments proposed within this research application will allow for me to gain valuable research training and experience using state of the art experimental techniques and will strengthen my ability to function as an independent research scientist.