Consequence and mechanism of diet-driven vagal remodeling on gut-brain feeding behavior

项目摘要 肥胖是我们这个时代的一个决定性的公共卫生问题。从根本上说，脂肪储存的增加是由 能量平衡失衡，有利于能量摄入而不是消耗。生理机制是 防止摄入过多的热量，但这些防御机制在面对现代食物时失败了。 促进食物摄入的环境。非侵入性策略缺乏有效性强调了这一点， 如限制热量摄入或药物治疗，以维持长期的减肥。因此，迫切需要 了解导致食物过度消费的病理生理学，并制定新的战略，以促进 减肥.迷走神经提供从肠道到大脑的营养摄入的直接通信。 当提供可口的热量时，去除瘦动物的迷走神经会导致显著的暴饮暴食 高密度饮食，表明迷走神经的保护作用，以防止过度消耗的热量。在肥胖症中， 肠道代谢信号到大脑的迷走神经通信受损，阻止迷走神经信号导致 高脂饮食动物的体重减轻。从保护免受， 促进肥胖的原因尚不清楚，但我们最近证明，长期食用高脂肪饮食 导致大脑中迷走神经纤维的解剖学重构。因此，我们提出了一个新的假设，迷走神经 肠-脑轴被重新编程以响应高脂肪饮食从而驱动肥胖。我们使用一种分子组合 和遗传学方法来解构感觉迷走神经到细胞成分的基础上，他们的网站， 神经支配，以充分阐明高脂肪喂养对迷走神经重塑的作用。在目标1中，我们评估了 饮食对迷走神经纤维解剖、突触功能和行为后果的影响，包括进餐终止和 食物的动机。在目标2和3中，我们考虑了饮食引起迷走神经重塑的机制。我们 假设肠道微生物群驱动的免疫反应触发了肠-脑轴的重新布线。这是 我们先前的工作和初步数据表明，异常的微生物群组成是必要的 并足以改变NTS中的迷走神经支配。在目标2中，我们将使用无菌大鼠和微生物群移植 为了确定1）微生物群生态失调是否足以进行迷走神经重塑，以及2）如果恢复共生微生物群， 可以使迷走神经信号、进食行为和体重正常化。在目标3中，我们将联合收割机 和分子工具来研究以迷走神经传入通路作为介质的免疫细胞的募集 饮食导致的迷走神经适应不良这些研究的完成将确定迷走神经重连作为一种新的途径， 肥胖的病因学，并建立微生物群和小胶质细胞作为体重发展的潜在工具 损失策略。 .

PROJECT SUMMARY Obesity is one of the defining public health problems of our time. At its root, increases in fat storage is caused by an imbalance in energy homeostasis, favoring energy intake over expenditure. Physiological mechanisms are in place to prevent excess caloric intake, yet these defense mechanisms fail in the face a modern food environment that promotes food intake. This is underscored by the lack of efficacy of non-invasive strategies, such as caloric restriction or medications, to sustain long-term weight loss. Thus, there is a critical need to understand the pathophysiology leading to food overconsumption and develop novel strategies to promote weight loss. The vagus nerve provides direct communication about nutrient intake from the gut to the brain. Removing of the vagus in lean animals results in significant overeating when presented with palatable calorie dense diets, suggesting a protective role of the vagus nerve to prevent overconsumption of calories. In obesity, vagal communication of gut metabolic cues to the brain is impaired, and preventing vagal signaling results in weight loss in animals fed high fat diet. The mechanisms for the switch from protection against, towards promoting obesity are unclear, but we have recently demonstrated that chronic consumption of high fat diet results in anatomical restructuring of vagal fibers in the brain. Therefore, we propose a new hypothesis that vagal gut-brain axis is reprogramed in response to high fat diets to drive obesity. We use a combination of molecular and genetic approaches to deconstruct the sensory vagus into cellular components based on their site of innervation to fully elucidate the role of high fat feeding on vagal remodeling. In aim 1 we assess the impact of diet on vagal fiber anatomy, synaptic function, and the behavioral consequences, including meal termination and motivation for food. In aims 2 and 3 we consider the mechanisms by which diet causes vagal remodeling. We hypothesize that a gut microbiota-driven immune response triggers the rewiring of the gut-brain axis. This is supported by our previous work and preliminary data showing abnormal microbiota composition is necessary and sufficient to alter vagal innervation in the NTS. In aim 2, we will use germ free rats and microbiota transplant to determine 1) if microbiota dysbiosis is sufficient for vagal remodeling, and 2) if restoring a symbiotic microbiota in obesity can normalize vagal signaling, feeding behavior and body weight. In aim 3 we will combine genetic and molecular tools to investigate the recruitment of immune cells with the vagal afferent pathway as mediators of diet-driven vagal maladaptation. Completion of these studies will identify vagal rewiring as a novel pathway in the etiology of obesity, and establish microbiota and microglia as potential tools for the development of weight loss strategies. .