The Impact of High Fat Diet on Brainstem Vagal Regulation

摘要： 目前对心脏副交感神经(或迷走神经)活动的理解明确地表明，迷走神经 心脏对心脏的活动和心脏迷走神经活动的稳态反射变化由心脏迷走神经运动介导 脑干的神经元(CVN)。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CVN在健康中的神经生理学，但在疾病中CVN功能障碍的可能性是 仍不清楚。这在我们对饮食和饮食之间复杂相互作用的理解上尤其正确 心血管功能。据估计，美国人每天从脂肪中多摄入600卡路里。 在最近的任何时间。这种摄入高脂肪食物的增加显著增加了罹患 发展中的心血管疾病。心血管疾病风险的一个显著特征是低心迷走神经 这种失衡的程度与风险、发病率和死亡率的增加密切相关。 我们实验室的初步数据显示，CVN的活性显著降低和抑制 在早期食用高脂肪食物时，向CVN的神经传递增加。这降低了CVN的活性 同时，心脏迷走神经对静息心率的贡献显著减少。迷走神经活动的减少 可以通过基因敲除介导抑制的受体的特定亚单位而被取消 越野车。关键的是，PKC抑制也消除了高脂饮食对迷走神经功能的影响，而且这种影响增加了 PKCδ活性可能是通过CVN上α-1肾上腺素受体活性增加而调节的。我们的整体 指导这一建议的假说是高脂饮食诱导的抑制性功能表达增加 CVN中的受体导致整体迷走神经活动进行性下降。然而，关键问题仍然存在， 包括对CVN的抑制增加的速度有多快，以及PKCδ异构体在 这种抑制。因此，这一建议将1)定量确定心脏迷走信号传递的时间 2)确定蛋白激酶Cδ在早期高脂饮食对血管紧张素转换酶功能影响中的作用。预期中的 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 以及迷走神经调节心率的机制。确定早期的机械性后果 HFD对迷走神经活动的研究可能导致生物标志物的发现，以及新疗法靶向的早期测试 疾病机制，而不是症状。

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.