The Impact of High Fat Diet on Brainstem Vagal Regulation

高脂肪饮食对脑干迷走神经调节的影响

• 批准号: 10599296
• 负责人: CARIE Renee BOYCHUK
• 金额: $ 1.68万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10599296
• 关键词: Adrenergic Receptor; Affect; American; Animals; Axon; Biological; Bradycardia; Brain Stem; Calories; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Cells; Characteristics; Chemoreceptors; Complex; Consumption; Data; Dependence; Diet; Disease; Early identification; Electrocardiogram; Electrophysiology (science); Fatty acid glycerol esters; Functional disorder; Ganglia; Generations; Genetic; Glutamates; Health; Heart; Heart Rate; Heart failure; High Fat Diet; Hypertension; Image; Knowledge; Laboratories; Mass Spectrum Analysis; Mediating; Mediator; Modality; Modeling; Molecular; Monitor; Morbidity - disease rate; Motor; Motor Activity; Motor Neurons; Mus; Myocardial dysfunction; Neuronal Dysfunction; Neurons; Nodal; Obesity; Pharmacology; Physiology; Play; Pressoreceptors; Protein Inhibition; Protein Isoforms; Protein Kinase C; Reflex action; Regulation; Rest; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Sensory; Signal Transduction; Symptoms; Synaptic Receptors; System; Telemetry; Testing; Time; Transgenic Mice; Transgenic Organisms; Viral; Work; biomarker discovery; cardiovascular disorder risk; experimental study; food consumption; gamma-Aminobutyric Acid; heart function; innovation; knock-down; mortality; motor neuron function; neurophysiology; neurotransmission; new therapeutic target; noradrenergic; novel; nucleus ambiguus; optogenetics; overexpression; patch clamp; pharmacologic; prevent; receptor; response; restraint; transcriptomics

ABSTRACT: Current understanding of cardiac parasympathetic (or vagal) activity unequivocally demonstrates that the vagal activity to the heart and homeostatic reflex changes in cardiac vagal activity are mediated by cardiac vagal motor neurons (CVNs) in the brainstem. Therefore, CVNs play an essential role in normal cardiovascular function. Despite our understanding of CVN neurophysiology in health, the potential for CVN dysfunction in diseases is still unclear. This is particularly true of our understanding of the complex interplay between diet and cardiovascular function. In some estimates, Americans are consuming 600 more calories from fat per day then any time in the recent past. This increased consumption of foods high in fat significantly elevated the risk of developing cardiovascular diseases. A distinctive hallmark of cardiovascular disease risk is low cardiac vagal signaling, and the extend of this imbalance correlates strongly with increasing risk morbidity and mortality. Preliminary data from our laboratory demonstrate that CVN activity is significantly reduced and inhibitory neurotransmission to CVNs is increased during early consumption of foods high in fat. This reduced CVN activity parallels a significant reduction in cardiac vagal contribution to resting heart rate. The reduction in vagal activity can be abolished through genetic knock down of a specific subunit of the receptors that mediate inhibition in CVNs. Critically, PKC inhibition also abolishes the influence of high fat diet on vagal function, and this increased PKCδ activity is likely mediated by increased activity of the alpha-1 adrenoreceptor on CVNs. Our overall hypothesis guiding this proposal is that high fat diet-induced increase in functional expression of inhibitory receptors in CVNs results in a progressive decline in overall vagal activity. However, critical questions remain, including how quickly does the increased inhibition of CVNs occur and what role does the PKCδ isoform play in this inhibition. Therefore, this proposal will 1) quantitively determine the timing of cardiac vagal signaling after high fat diet, and 2) establish the role of PKCδ in the effects of early HFD on CVN function. The anticipated results of these experiments will provide fundamental details in our understanding of cardiac vagal regulation and mechanisms responsible for vagal regulation of heart rate. Identifying the early mechanistic consequences of HFD on vagal activity could lead to the discovery of biomarkers, and early testing of new therapeutics targeting disease mechanisms, rather than symptoms.

抽象的： 当前对心脏副交感神经（或迷走神经）活性的理解明确表明了迷走神经 心脏迷走神经活动中心脏和稳态反射变化的活性由心迷走运动介导 脑干中的神经元（CVN）。因此，CVN在正常的心血管功能中起着至关重要的作用。 尽管我们了解了CVN神经生理学在健康方面，但疾病中CVN功能障碍的可能 仍然不清楚。我们对饮食和饮食之间复杂相互作用的理解尤其如此 心血管功能。在某些估计中，美国人每天要消耗600卡路里的卡路里 最近的任何时候。高脂肪的食物消费的增加显着升高了 发展心血管疾病。心血管疾病风险的独特标志是低心脏迷走神经 信号传导以及这种不平衡的扩展与风险发病率和死亡率的增加密切相关。 我们实验室的初步数据表明，CVN活性显着降低和抑制作用 在早期食用高脂肪的食物期间，神经传递的CVN会增加。这减少了CVN活性 与静息心​​率的心脏迷走神经贡献显着降低。迷走神经活动的减少 可以通过遗传敲低接收器的特定亚基来消除媒体抑制 CVN。至关重要的是，PKC抑制也废除了高脂饮食对迷走神经功能的影响，这增加了 PKCδ活性可能是由α-1肾上腺受体在CVNS上的活性增加而介导的。我们的整体 指导该提议的假设是高脂饮食诱导的抑制功能表达的增加 CVN中的接收器导致整体迷走神经活动的逐渐下降。但是，仍然存在关键问题， 包括增加CVN的抑制作用的速度以及PKCδ同工型在 这种抑制作用。因此，该建议将1）定量确定心迷走神经信号的时机 高脂饮食和2）确定PKCδ在早期HFD对CVN功能的影响中的作用。预期 这些实验的结果将在我们对心脏迷走神经调节的理解中提供基本细节 以及负责迷走神经心率调节的机制。确定早期的机械后果 HFD在迷走神经活动上可能会导致生物标志物的发现，并早期测试新的治疗剂 疾病机制，而不是症状。