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

• 批准号: 10581535
• 负责人: Claire de La Serre
• 金额: $ 42.57万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581535
• 关键词: Ablation; Afferent Neurons; Afferent Pathways; Anatomy; Animal Feed; 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; Metabolic; Microglia; Modeling; Modernization; Molecular; Motivation; Mus; Neurons; Neurosciences; Nodose Ganglion; Nucleus solitarius; Nutrient; Obesity; Obesity Epidemic; Pathogenesis; Pathway interactions; Peripheral; Pharmaceutical Preparations; Physiological; Public Health; Publishing; Rattus; Research; Rewards; Role; Sensory; Signal Transduction; Site; Structure; Testing; Therapeutic; Thinness; Time; Vagotomy; Vagus nerve structure; Viral; Virus; Weight Gain; Withdrawal; Work; 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; inducible Cre; innovation; insight; microbiota; microbiota transplantation; nerve supply; neural; novel; novel strategies; obesity development; obesity treatment; postsynaptic; prevent; recruit; response; restoration; synaptic function; tool; tool development; weight loss intervention; Ablation; Afferent Neurons; Afferent Pathways; Anatomy; Animal Feed; 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; Metabolic; Microglia; Modeling; Modernization; Molecular; Motivation; Mus; Neurons; Neurosciences; Nodose Ganglion; Nucleus solitarius; Nutrient; Obesity; Obesity Epidemic; Pathogenesis; Pathway interactions; Peripheral; Pharmaceutical Preparations; Physiological; Public Health; Publishing; Rattus; Research; Rewards; Role; Sensory; Signal Transduction; Site; Structure; Testing; Therapeutic; Thinness; Time; Vagotomy; Vagus nerve structure; Viral; Virus; Weight Gain; Withdrawal; Work; 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; inducible Cre; innovation; insight; microbiota; microbiota transplantation; nerve supply; neural; novel; novel strategies; obesity development; obesity treatment; postsynaptic; prevent; recruit; response; restoration; synaptic function; tool; tool development; weight loss intervention

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. .

项目摘要 肥胖是我们这个时代定义的公共卫生问题之一。从根本上讲，脂肪存储的增加是引起的 通过能量稳态的失衡，有利于能量摄入而不是支出。生理机制是 防止过量热量摄入量的适当，但这些防御机制在面前失败了现代食物 促进食物摄入的环境。这是由于缺乏非侵入性策略的功效而强调了这一点， 例如热量限制或药物，以维持长期的体重减轻。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。迷走神经提供了有关从肠道到大脑的营养摄入量的直接沟通。 出现可口卡路里时，瘦动物中的迷走神经的消除会导致大量暴饮暴食 致密饮食，表明迷走神经的保护作用以防止卡路里的消耗过度。在肥胖中， 肠道代谢线索与大脑的迷走神经通信受到损害，防止迷走神经信号导致 动物体重减轻喂养高脂饮食。从保护转移到的机制 促进肥胖尚不清楚，但我们最近证明了长期消费高脂饮食 导致大脑迷走神经纤维的解剖结构。因此，我们提出了一个新假设，即迷走神经 肠脑轴是针对高脂肪饮食以驱动肥胖的响应而重编程的。我们结合了分子 以及基于其位置 神经支配完全阐明了高脂肪进食对迷走神经重塑的作用。在AIM 1中，我们评估了 饮食迷走神经解剖学，突触功能和行为后果，包括饮食终止和 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 假设肠道微生物群驱动的免疫反应会触发肠道轴的重新布线。这是 在我们以前的工作和初步数据的支持下，有必要的菌群组成是必要的 足以改变NTS中的迷走神经支配。在AIM 2中，我们将使用无菌大鼠和微生物群移植 确定1）菌群营养不良是否足以进行迷走神经重塑； 2）如果恢复共生微生物群 在肥胖症中，可以使迷走神经信号传导正常化，喂养行为和体重。在AIM 3中，我们将结合遗传 和分子工具，用于研究带有迷走神经传入途径的免疫细胞作为介体的募集 饮食驱动的迷走神经疾病。这些研究的完成将确定迷走神经的重新布线是一种新的途径 肥胖症的病因，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。 。