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

饮食驱动的迷走神经重塑对肠脑进食行为的影响和机制

基本信息

批准号：
10197124
负责人：
Claire de La Serre
金额：
$ 44.72万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197124
关键词：
Afferent Neurons Afferent Pathways Anatomy Animals Antibiotic Therapy Behavioral Body Weight Body Weight decreased Brain C Fiber Caloric Restriction Calories Caspase Cell Nucleus Cells Chronic Communication Consumption Cues Data Deafferentation procedure Defense Mechanisms Diet Eating Emotional Energy Intake Enterobacteria phage P1 Cre recombinase Etiology Expenditure Face Fatty acid glycerol esters Feeding behaviors Fiber Food Functional disorder Genetic Germ-Free High Fat Diet Homeostasis Human Hyperphagia Immune Immune response Impairment Inflammatory Intake Knowledge Label Maps Medial Mediator of activation protein Metabolic Microglia Modernization Molecular Molecular Genetics Motivation Mus Neurons Neurosciences Nodose Ganglion Nucleus solitarius Nutrient Obesity Obesity Epidemic Palate Pathogenesis Pathway interactions Peripheral Pharmaceutical Preparations Physiological Plant Roots Public Health Publishing Rattus Research Rewards Role Sensory Signal Transduction Site Structure Synapses Testing Therapeutic Thinness Time Vagotomy Vagus nerve structure Viral Virus Weight Gain Withdrawal Work base brain circuitry combinatorial diet-induced obesity dysbiosis economic cost effective therapy excessive weight gain fecal transplantation feeding food environment genetic approach gut microbiota gut-brain axis hindbrain innovation insight microbiota microbiota transplantation nerve supply novel novel strategies obesity development obesity treatment prevent recruit relating to nervous system response restoration synaptic function tool tool development weight loss intervention

项目摘要

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. .

项目概要肥胖是我们这个时代决定性的公共卫生问题之一。从根本上来说，导致脂肪储存增加由于能量稳态不平衡，有利于能量摄入而不是支出。生理机制是可以防止热量摄入过多，但这些防御机制在面对现代食物时却失效了促进食物摄入的环境。非侵入性策略缺乏功效凸显了这一点，例如热量限制或药物治疗，以维持长期减肥。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策略来促进减肥。迷走神经提供从肠道到大脑的营养摄入的直接通讯。当提供可口的卡路里时，去除瘦动物的迷走神经会导致严重的暴饮暴食密集饮食，表明迷走神经具有防止卡路里过度消耗的保护作用。在肥胖的情况下，肠道代谢信号与大脑的迷走神经通讯受到损害，并且阻止迷走神经信号传导会导致喂食高脂肪饮食的动物体重减轻。从保护转向的机制促进肥胖的尚不清楚，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结构重组。因此，我们提出一个新的假设：迷走神经肠脑轴因高脂肪饮食而被重新编程，从而导致肥胖。我们使用分子组合以及根据感觉迷走神经的位置将感觉迷走神经解构为细胞成分的遗传方法神经支配充分阐明高脂肪喂养对迷走神经重塑的作用。在目标 1 中，我们评估了以下方面的影响：饮食对迷走神经纤维解剖学、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肠-脑轴的重新布线。这是我们之前的工作和显示异常微生物群组成的初步数据的支持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移植确定 1) 微生物群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群在肥胖症中可以使迷走神经信号、进食行为和体重正常化。在目标 3 中，我们将结合遗传和分子工具来研究以迷走神经传入途径作为介质的免疫细胞的招募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布线是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。。