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

项目总结 获得高热量、美味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如何失调方面，人们知之甚少。 关于在接触肥胖饮食时发生的早期事件以及这最终可能如何促成 肥胖症的进展。我们小组和其他人进行的研究评估了 啮齿类动物获得高脂肪饮食(HFD)已显示出摄食模式随时间的变化。具体来说， 在接触HFD后，啮齿动物经历了一段短暂的吞噬过度时期(24-48小时)，然后是 恢复正常食欲(72小时)，然后逐渐恢复过高的卡路里摄入量 在一段时间里。阐明了调节不同摄食模式的机制 接触HFD的早期阶段和肥胖之前可以识别可能是 用于预防或干预肥胖的治疗。此应用程序旨在 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 和后脑前胰高血糖素原(PPG)神经元在控制摄食行为。面包车扮演着关键角色 将饱腹感和其他与食物摄取有关的信号从外周传递到中枢神经系统 (CNS)。孤束核(NTS)中的PPG神经元是胰升糖素样肽-1的主要来源 (GLP-1)，GLP-1是一种饱腹感因子，通过作用于GLP1受体而减少卡路里摄入 (GLP1R)。Vans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以及 对控制食物摄入量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VAN-PPG相互作用的时间依赖性影响 假设VAN-PPG神经元结合减少与过度吞噬反应有关 HFD。实验2建议具体描述PPG神经元对摄食模式的影响 通过选择性消融/抑制NTS PPG神经元给予HFD。我们假设 NTS PPG神经元的丢失/抑制将加剧HFD给药相关的吞噬功能亢进 并增加恢复正常食欲的时间。在这项研究申请中提出的实验将 允许我使用最先进的实验技术获得有价值的研究、培训和经验 并将增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.