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: 10445142
• 负责人: CARIE Renee BOYCHUK
• 金额: $ 43.4万
• 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 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445142
• 关键词: Address; 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; Electrocardiogram; Electrophysiology (science); Fatty acid glycerol esters; Functional disorder; Ganglia; Generations; Genetic; Glutamates; Health; Heart; Heart Rate; Heart failure; High Fat Diet; Hypertension; Knowledge; Laboratories; Lead; Mediating; Mediator of activation protein; Modality; Modeling; Molecular; Monitor; Morbidity - disease rate; Motor; Motor Activity; Motor Neurons; Mus; Myocardial 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; System; Telemetry; Testing; Time; Transgenic Mice; Transgenic Organisms; Viral; Work; base; biomarker discovery; cardiovascular disorder risk; experimental study; food consumption; gamma-Aminobutyric Acid; heart function; innovation; knock-down; mass spectrometric imaging; mortality; motor neuron function; neurophysiology; neurotransmission; new therapeutic target; noradrenergic; novel; nucleus ambiguus; optogenetics; overexpression; patch clamp; 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.

摘要： 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 心脏迷走神经活动和心脏迷走神经活动中的稳态反射变化由心脏迷走神经运动介导 脑干中的神经元（CVNs）。因此，CVN在正常心血管功能中起着至关重要的作用。 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。 目前仍不清楚.我们对饮食与健康之间复杂相互作用的理解尤其如此， 心血管功能据估计，美国人每天从脂肪中消耗的热量比 任何时间都没有高脂肪食物的摄入量增加， 发展成心血管疾病。心血管疾病风险的一个独特标志是心脏迷走神经功能低下 这种不平衡的程度与发病率和死亡率的增加密切相关。 来自我们实验室的初步数据表明，CVN活性显著降低，并且具有抑制作用。 在早期食用高脂肪食物期间，对CVN的神经传递增加。这降低了CVN活性 与心脏迷走神经对静息心率贡献的显著减少平行。迷走神经活动的减少 可以通过遗传敲低介导抑制的受体的特定亚基来消除， CVN。重要的是，PKC抑制还消除了高脂饮食对迷走神经功能的影响，这增加了 PKCδ活性可能由CVN上α-1肾上腺素受体活性增加介导。我们的整体 指导这一建议的假设是高脂肪饮食诱导的抑制蛋白功能表达的增加， 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抑制作用的增强有多快，PKCδ亚型在 这种抑制。因此，该提议将1）定量地确定心脏迷走神经信号传导的时间， 高脂饮食，2）建立PKCδ在早期HFD对CVN功能影响中的作用。预期 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的细节 以及负责心率迷走神经调节的机制。识别早期的机械后果 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。