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

HFD 驱动 AgRP 神经元基因表达的活动依赖性调节以促进 DIO

• 批准号: 10439962
• 负责人: Austin Korgan
• 金额: $ 7.05万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439962
• 关键词: Acute; Appetitive Behavior; Automobile Driving; Behavior; Bioinformatics; Body Weight; Body Weight decreased; Brain region; Caloric Restriction; Candidate Disease Gene; Chronic; Consumption; Coupling; Data; Development; Diabetes Mellitus; Diet; Early Intervention; Eating; Electrophysiology (science); Energy Intake; Epidemic; Failure; Fasting; Feeding behaviors; Food; Frequencies; Future; Gene Expression Regulation; Genes; Genetic Transcription; Heart Diseases; High Fat Diet; Homeostasis; Hormones; Hyperphagia; Hypertension; Hypothalamic structure; Laboratories; Leptin; Light; Maintenance; Maps; Medial Dorsal Nucleus; Mediating; Mediator of activation protein; Metabolic stress; Metabolism; Mus; Nervous System control; Neuraxis; Neuronal Plasticity; Neurons; Obesity; Output; Pathogenesis; Peptides; Phenotype; Population; Prevention; Public Health; Regulation; Reporting; Research; Rodent; Role; Signal Transduction; Structure of nucleus infundibularis hypothalami; Synapses; Synaptic plasticity; Time; United States; Validation; Viral; Weight; Weight Gain; combat; comorbidity; diet-induced obesity; dietary; effective therapy; energy balance; experimental study; feeding; gene therapy; innovation; mRNA sequencing; neuromechanism; neuronal circuitry; neuronal excitability; neuropeptide Y; new therapeutic target; novel; novel therapeutic intervention; obesity treatment; obesogenic; optogenetics; postsynaptic; presynaptic; programs; relating to nervous system; response; saturated fat; sugar; transcriptome sequencing; validation studies

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.

项目概要/摘要 肥胖及其相关合并症（糖尿病、心脏病、高血压等）目前困扰着人们 美国有超过 1.14 亿人，缺乏有效的治疗方案反映在 预计到 2030 年这一数字将增加到近 1.5 亿。热量摄入过多是肥胖的主要原因， 然而，驱动过量食物摄入的神经机制（并且可能是 肥胖）仍未确定。先前对啮齿动物的研究一致表明，饮食中富含饱和脂肪和 糖会增加负责维持能量稳态的神经元回路的兴奋性。这增加了 兴奋性与食物摄入量、体重和瘦素不敏感的增加相一致。不过，时间进程 这些影响以及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，以及减肥后或体重增加困难 减肥。 弓状核中的刺鼠相关肽（AgRP）/神经肽-Y（NPY）神经元 下丘脑是负责食物摄入的主要神经元群。 AgRP 神经活动迅速且 可靠地启动食物寻找行为，通常通过禁食或热量限制来增强这种行为 开始进食后消退。此外，AgRP 神经元活性在以下情况下持续升高： 高脂肪饮食（HFD）喂养。我们的初步数据表明短期和长期 HFD 对健康的影响不同 AgRP/NPY 神经元的突触可塑性和信号整合。具体来说，短期（2 天）HFD 增加 AgRP 神经元的兴奋性信号传导。然而，长期（8 周）HFD 会导致持续的 AgRP 神经损伤 尽管抑制信号传导增加，但仍具有活性。由于这些影响背后的机制仍然很差 据了解，我的目标是利用先前绘制的兴奋性和抑制性输入来探测 HFD 诱导的 突触可塑性和 AgRP 神经元活动。我还将使用 AgRP 特异性 RNA 测序来识别 与短期和长期 HFD 喂养相关的转录变化。通过将电生理学与 –组学方法，我将确定先验基因并优先考虑新的候选基因以进行验证研究 短期和长期 HFD 喂养的小鼠。这些将重点关注报告的兴奋性或抑制性输入的变化 以及进食行为和体重增加的表型变化。 饮食引起的 AgRP/NPY 神经元群内神经机制的改变至关重要 了解体内平衡失调。识别 HFD 诱发的潜在机制 肥胖对于未来开发对抗饮食引起的肥胖的新治疗策略至关重要。 总体而言，该研究计划提出的实验预计会发现以前未描述过的 急性或慢性食用致胖饮食后食欲行为的刺激剂。