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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：
10375565
负责人：
Claire de La Serre
金额：
$ 44.66万
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/10375565
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. .

项目总结