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

项目总结 肥胖是我们这个时代决定性的公共健康问题之一。从根本上说，脂肪储存的增加是由 由于能量动态平衡的不平衡，有利于能量摄入而不是支出。生理机制是 防止过多的卡路里摄入，然而这些防御机制在现代食物面前失败了 促进食物摄取的环境。非侵入性策略缺乏有效性就突显了这一点， 例如卡路里限制或药物治疗，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机制，并开发新的策略来促进 减肥。迷走神经提供从肠道到大脑的营养摄取的直接通信。 去掉瘦小动物的迷走神经，当摄入适口的卡路里时，会导致明显的暴食。 密集的饮食，表明迷走神经的保护作用，以防止卡路里的过度消耗。在肥胖方面， 肠道代谢信号与大脑的迷走神经联系受损，阻止迷走神经信号传递会导致 喂食高脂肪饲料的动物体重减轻。从防护转向防护的机制 促进肥胖的原因尚不清楚，但我们最近已经证明，长期食用高脂肪饮食 导致大脑迷走神经纤维的解剖学重组。因此，我们提出了一个新的假说，迷走神经 肠道-脑轴被重新编程，以应对高脂肪饮食导致的肥胖。我们使用的是分子的组合 以及根据感觉迷走神经的位置将迷走神经分解为细胞成分的遗传方法 充分阐明高脂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，包括终止进餐和 对食物的动力。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 假设肠道微生物区系驱动的免疫反应触发了肠道-脑轴的重新连接。这是 在我们之前的工作和初步数据的支持下，显示异常微生物区系组成是必要的 足以改变NTS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区系移植 确定1)微生物区系失调是否足以进行迷走神经重塑，以及2)是否恢复共生微生物区系 肥胖可以使迷走神经信号、摄食行为和体重正常化。在目标3中，我们将结合基因 以及研究以迷走神经传入通路为介体的免疫细胞招募的分子工具 饮食驱动的迷走神经适应不良。这些研究的完成将确定迷走神经重新连接是一种新的 肥胖的病因，并建立微生物区系和小胶质细胞作为体重发育的潜在工具 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. .