The Role of the Paraventricular Hypothalamus in the Rhythmic Regulation of Feeding and Metabolism

室旁下丘脑在摄食和代谢节律调节中的作用

基本信息

批准号：
10464689
负责人：
Rachel Van Drunen
金额：
$ 3.42万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2022-02-08 至 2024-02-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10464689
关键词：
ARNT gene ARNTL gene Address Alzheimer&apos s Disease Behavior Behavior Therapy Behavioral Bilateral Binding Biological Biological Clocks Body Weight Brain Cells ChIP-seq Circadian Dysregulation Circadian Rhythms Consumption Corticotropin-Releasing Hormone Data Defect Dependence Desire for food Eating Electrophysiology (science)Endocrine Energy Intake Energy Metabolism Epidemic Feeding Patterns Genes Genomic approach Growth High Fat Diet Homeostasis Homologous Gene Hypothalamic structure Impaired health Individual Injections Investigation Knock-out Long-Term Effects Measures Mediating Metabolism Methods Mind Molecular Motor Activity Mus Muscle Neurons Non-Insulin-Dependent Diabetes Mellitus Nutrient Obese Mice Obesity Output Pathogenesis Pattern Periodicity Peripheral Pharmacological Treatment Pharmacology Phenotype Play Process Proteins Regulation Research RiboTag Rodent Model Role Satiation Stress Structure of nucleus infundibularis hypothalami Testing Therapeutic Time Time-restricted feeding Tissues Transcript Translating Viral Work adenoviral-mediated adult obesity behavioral pharmacology cardiovascular disorder risk circadian circadian biology circadian pacemaker combat cost diet-induced obesity energy balance epidemiology study feeding global health mouse model neural circuit neuromechanism novel obesity treatment obesogenic paraventricular nucleus relating to nervous system side effect suprachiasmatic nucleus time use transcription factor

项目摘要

The Role of the Paraventricular Hypothalamus in the Rhythmic Regulation of Feeding and Metabolism Obesity has reached epic proportions, in the US alone, over 70 million adults are obese. Despite the alarming growth of this worldwide epidemic, the current therapeutics for obesity are limited in efficacy. For centuries, overconsumption has been an evident culprit in obesity pathogenesis; however, the underlying cause of obesity is a multifaceted biological problem, which has yet to be fully understood. Recent research has revealed that the intrinsic biological clocks throughout the body are essential to the regulation of feeding and body weight homeostasis. Large scale epidemiological studies on shift workers show that disruption of the natural circadian patterns predisposes individuals to adiposity. Other research on rodent models of diet-induced obesity (DIO) show an initial blunting of diurnal feeding and locomotor activity on high fat diet feeding, indicating a bidirectional relationship between obesity and the circadian clock. Ultimately, both shift workers and DIO mice have widespread desynchrony across peripheral tissues and the central clock. This decoupling suggests that body- wide clock desynchrony may be involved in the pathogenesis of obesity. This proposal is centered on understanding the circadian mechanisms that drive rhythmic energy intake and expenditure. More specifically, the proposal focuses on the paraventricular nucleus (PVN) of the hypothalamus for its vital function as both integrator and regulator of satiety and metabolism. Once thought to function merely as a peripheral clock to the master clock (the suprachiasmatic nucleus [SCN]), the PVN has been identified to have its own intrinsic clock. Electrophysiological recordings reveal diurnal fluctuations in the activity of inhibitory GABAergic neurons relaying nutrient information to the PVN. These fluctuations appear to be driven by BMAL1 (Brain and Muscle ARNT- Like1), an essential circadian transcription factor for maintaining robust rhythms in a variety of cells across the body. Importantly, our preliminary data demonstrates that inducible loss of BMAL1 function in the PVN corresponds to arrhythmic food intake in mice. This proposal will investigate the role of BMAL1 driven mechanisms in the PVN as a central driver for governing patterns of energy balance. We will attempt to define the respective roles of the PVN and SCN in mediating diurnal energy intake and metabolism. In addition, to further characterize the interworking of the PVN rhythmicity, the proposal will also address which PVN neuronal subtypes, such as corticotrophin releasing hormone (CRH)-expressing neurons, drive diurnal energy intake and metabolism. At the molecular level, we will use high throughput genomic approaches to illuminate the molecular machinery by which BMAL1 regulates the PVN's rhythmic functions. The successful completion of these aims will establish for the first time a previously unknown role of the PVN as a rhythmic regulator of energy intake and body weight homeostasis. In all, a complete understanding of the neural mechanisms governing consumption and energy homeostasis is needed to develop pharmacological and behavioral therapeutics to effectively combat obesity.

室旁下丘脑在摄食和代谢节律调节中的作用肥胖症已达到史无前例的程度，仅在美国，就有超过 7000 万成年人患有肥胖症。尽管令人震惊随着这一全球性流行病的蔓延，目前的肥胖疗法疗效有限。几个世纪以来，过度消费是肥胖发病的明显罪魁祸首；然而，肥胖的根本原因这是一个多方面的生物学问题，尚未得到充分理解。最近的研究表明，全身固有的生物钟对于调节进食和体重至关重要体内平衡。对轮班工人的大规模流行病学研究表明，自然昼夜节律的破坏模式使人容易肥胖。关于饮食诱导肥胖（DIO）的啮齿动物模型的其他研究显示高脂肪饮食喂养的昼夜喂养和运动活动最初减弱，表明双向肥胖与生物钟之间的关系。最终，轮班工人和 DIO 小鼠都周围组织和中央时钟之间广泛的不同步。这种解耦表明身体宽时钟不同步可能与肥胖的发病机制有关。该提案的核心是了解驱动有节奏的能量摄入和消耗的昼夜节律机制。更具体地说，该提案重点关注下丘脑的室旁核（PVN），因为它的重要功能既是饱腹感和新陈代谢的整合者和调节者。曾经被认为仅仅充当外围时钟的作用主时钟（视交叉上核 [SCN]），PVN 已被确定有其自己的内在时钟。电生理记录揭示了抑制性 GABA 神经元传递活动的昼夜波动向 PVN 发送营养信息。这些波动似乎是由 BMAL1（大脑和肌肉 ARNT- Like1)，一种重要的昼夜节律转录因子，用于维持多种细胞的稳健节律身体。重要的是，我们的初步数据表明 PVN 中 BMAL1 功能的诱导性丧失对应于小鼠的无节律食物摄入。该提案将调查 BMAL1 驱动的作用 PVN 中的机制作为能源平衡治理模式的核心驱动力。我们将尝试定义 PVN 和 SCN 在介导昼夜能量摄入和代谢中各自的作用。此外进一步表征 PVN 节律性的相互作用，该提案还将解决 PVN 神经元亚型，例如表达促肾上腺皮质激素释放激素（CRH）的神经元，驱动昼夜能量摄入和代谢。在分子水平上，我们将使用高通量基因组方法来阐明分子水平 BMAL1 调节 PVN 节律功能的机制。这些目标的顺利完成将首次确立 PVN 作为能量摄入和节律调节器的先前未知的作用体重稳态。总而言之，全面了解控制消费的神经机制需要能量稳态来开发药理学和行为疗法以有效对抗肥胖。