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

基本信息

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
项目类别：
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

项目摘要

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：目前对心脏副交感神经（或迷走神经）活动的理解明确表明，迷走神经心脏的活动和心脏迷走神经活动的稳态反射变化是由心脏迷走神经运动介导的脑干中的神经元（CVN）因此，CVN 在正常心血管功能中发挥着重要作用。尽管我们了解健康中的 CVN 神经生理学，但疾病中 CVN 功能障碍的可能性仍然存在。我们对饮食与饮食之间复杂相互作用的理解尤其如此。据估计，美国人每天从脂肪中摄入的热量比以前多 600 卡路里。在最近的任何时候，增加高脂肪食物的摄入都会显着增加患此病的风险。心血管疾病风险的一个显着特征是心脏迷走神经低。信号传导，并且这种不平衡的程度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 活性显着降低并具有抑制作用早期食用高脂肪食物时，CVN 的神经传递会增加，从而降低了 CVN 的活性。与心脏迷走神经对静息心率的贡献显着减少相平行的是迷走神经活动的减少。可以通过基因敲除介导抑制作用的受体的特定亚基来消除重要的是，PKC 抑制还消除了高脂肪饮食对迷走神经功能的影响，并且这增加了迷走神经功能。 PKCδ 活性可能是由 CVN 上 α-1 肾上腺素受体活性增加介导的。指导这一提议的假设是高脂肪饮食诱导抑制性功能表达的增加 CVN 中的受体导致总体迷走神经活动逐渐下降然而，关键问题仍然存在。包括 CVN 抑制增加的速度有多快以及 PKCδ 亚型在其中发挥什么作用因此，该提案将 1) 定量确定心脏迷走神经信号传导后的时间。高脂肪饮食，2) 确定 PKCδ 在早期 HFD 对 CVN 功能的影响中的作用。这些实验的结果将为我们理解心脏迷走神经调节提供基本细节以及负责心率迷走神经调节的机制。 HFD 对迷走神经活动的影响可能会导致生物标志物的发现，以及新疗法的早期测试疾病机制，而不是症状。