Activity Dependent Regulation of Gene Expression in AgRP Neurons is Driven by HFD to Promote DIO

项目摘要/摘要 肥胖及其相关并发症(糖尿病、心脏病、高血压等)目前正在折磨着 美国有超过1.14亿人，缺乏有效的治疗选择，这反映在 预计到2030年，这一数字将增加到近1.5亿。摄入过多的卡路里是肥胖的主要原因， 然而，驱动过量食物摄入的神经机制(可能是 肥胖症)仍未确定。先前对啮齿动物的研究一直表明，高饱和脂肪和高脂肪饮食 糖增加负责维持能量平衡的神经元回路的兴奋性。这增加了 兴奋性与食物摄入量增加、体重增加和瘦素不敏感相一致。然而，时间进程 对于这些影响和潜在突触变化的重要性尚不清楚。这些变化可能会推动 饮食引起的肥胖的发展和维持，以及减肥或体重增加的困难 减肥。 大鼠弓状核内的AgRP/NPY神经元 下丘脑是负责食物摄取的主要神经元群体。AgRP神经活动迅速和 可靠地启动寻找食物的行为，这通常通过禁食或限制卡路里和 在开始进餐时消退。此外，AgRP神经元的活性在下列情况下持续升高 高脂饮食(HFD)喂养。我们的初步数据表明，HFD的短期和长期影响不同 AgRP/NPY神经元的突触可塑性和信号整合。具体地说，短期(2天)HFD增加 给AgRP神经元的兴奋性信号。然而，长期(8周)HFD会导致持续的AgRP神经 尽管抑制信号增加，但仍有活性。由于这些效应背后的机制仍然很差 理解，我的目标是利用先前映射的兴奋性和抑制性输入来探测HFD诱导的 突触可塑性和AgRP神经元活性。我还将使用AgRP特定的RNA测序来识别 与短期和长期饲喂HFD有关的转录变化。通过将电生理学与 -组学方法，我将确定先验基因，并优先选择新的候选基因进行验证研究 短期和长期饲喂HFD的小鼠。这些将集中在报道的兴奋性或抑制性输入的改变上。 以及摄食行为和体重增加的表型变化。 饮食诱导的AgRP/NPY神经元群体内神经机制的改变是至关重要的 以了解体内平衡失调。HFD诱导的潜在机制的确定 肥胖对于未来开发新的治疗策略来对抗饮食诱导的肥胖至关重要。 总体而言，这项研究计划提出了一些实验，这些实验预计会发现以前没有描述过的 在急性或长期食用肥胖饮食后的食欲行为的刺激因素。

PROJECT SUMMARY/ABSTRACT Obesity and its related comorbidities (diabetes, heart disease, hypertension, etc.) currently afflicts more than 114 million people in the United States and the absence of effective treatment options is reflected by the projected rise to nearly 150 million people by 2030. Excess caloric intake is the primary cause of obesity, however, the neural mechanisms driving superfluous food intake (and likely underlie the pathogenesis of obesity) remain unidentified. Previous studies in rodents consistently show that diets high in saturated fat and sugar increase excitability of neuronal circuits responsible for maintaining energy homeostasis. This increased excitability coincides with increased food intake, body-weight, and leptin insensitivity. However, the time course for these effects and the importance of underlying synaptic changes are unclear. These changes likely drive development and maintenance of diet-induced obesity, as well as difficulty losing weight or weight gain after weight loss. Agouti-related peptide (AgRP)/ neuropeptide-Y (NPY) neurons in the arcuate nucleus of the hypothalamus are the primary neuronal population responsible for food intake. AgRP neural activity rapidly and reliably initiates food seeking behavior, which is typically enhanced by fasting or caloric restriction and subsides upon initiation of meal consumption. Further, AgRP neuronal activity is consistently elevated following high fat diet (HFD) feeding. Our preliminary data suggest divergent effects of short- and long-term HFD on synaptic plasticity and signal integration to AgRP/NPY neurons. Specifically, short-term (2 day) HFD increases excitatory signaling to AgRP neurons. However, long-term (8 weeks) HFD results in sustained AgRP neural activity despite increased inhibitory signaling. Since the mechanisms underlying these effects remain poorly understood, my objective is to utilize previously mapped excitatory and inhibitory inputs to probe HFD-induced synaptic plasticity and AgRP neuronal activity. I will also use AgRP-specific RNA sequencing to identify transcriptional changes related to both short- and long-term HFD feeding. By pairing electrophysiology with an –omics approach, I will identify a priori genes and prioritize novel candidate genes for validation studies in both short- and long-term HFD fed mice. These will focus on the reported alterations to excitatory or inhibitory inputs and phenotypic changes in feeding behavior and weight gain. Diet-induced alterations to neural mechanisms within the AgRP/NPY neuronal population, are crucial for understanding homeostatic dysregulation. Identification of the underlying mechanisms driving HFD-induced obesity are critical for future development of novel therapeutic strategies to combat diet-induced obesity. Overall, this research program proposes experiments that anticipate the discovery of previously undescribed stimulators of appetitive behavior following acute or chronic consumption of obesogenic diet.