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

• 批准号: 10570840
• 负责人: Rachel Van Drunen
• 金额: $ 3.52万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 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/10570840
• 关键词: ARNT gene; ARNTL gene; Address; Alzheimer' s Disease; Arrhythmia; 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; Phenotype; Play; Process; Proteins; Regulation; Research; RiboTag; Rodent Model; Role; Rotation; Satiation; Stress; Structure of nucleus infundibularis hypothalami; Testing; Therapeutic; Time; Time-restricted feeding; Tissues; Transcript; Translating; Viral; Work; adenoviral mediated; adult obesity; brain tissue; cardiovascular disorder risk; circadian; circadian biology; circadian pacemaker; combat; cost; diet-induced obesity; energy balance; epidemiology study; feeding; global health; inducible Cre; mouse model; neural; neural circuit; neuromechanism; novel; obesity treatment; obesogenic; paraventricular nucleus; pharmacologic; side effect; suprachiasmatic nucleus; time use; transcription factor

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.

下丘脑室旁核在摄食和代谢节律调节中的作用 肥胖已经达到了史诗般的比例，仅在美国，就有超过7000万成年人肥胖。尽管有令人震惊的 随着这种全球流行病的增长，目前用于肥胖症的治疗方法在功效上是有限的。几个世纪以来， 过度消费是肥胖症发病机制中的明显罪魁祸首;然而，肥胖症的根本原因 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， 整个身体的内在生物钟对摄食和体重的调节至关重要 体内平衡对倒班工人的大规模流行病学研究表明， 这种模式使人容易肥胖。饮食诱导肥胖（DIO）啮齿动物模型的其他研究 显示高脂饮食喂养的昼夜摄食和自发活动的初始钝化，表明双向 肥胖和生物钟之间的关系最终，轮班工人和DIO小鼠都有 在外周组织和中央时钟上广泛分布。这种分离表明，身体- 肥胖症的发病机制可能与生物钟紊乱有关。该提案以 了解驱动能量摄入和消耗节律的昼夜节律机制。更具体地说， 该建议集中在下丘脑室旁核（PVN）的重要功能， 饱腹感和新陈代谢的整合和调节。曾经被认为只是作为一个外围时钟的功能， 主时钟（视交叉上核[SCN]），PVN已被确定有自己的内在时钟。 电生理记录揭示了抑制性GABA能神经元中继活动的昼夜波动 向PVN提供营养信息。这些波动似乎是由BMAL1（大脑和肌肉ARNT-1）驱动的。 Like1），一种重要的昼夜节律转录因子，用于维持跨细胞的各种细胞的稳健节律。 身体重要的是，我们的初步数据表明，PVN中BMAL1功能的诱导性缺失 对应于小鼠的摄食量。本提案将研究BMAL1驱动的 PVN中的机制作为管理能量平衡模式的中心驱动力。我们将尝试定义 PVN和SCN在介导昼夜能量摄入和代谢中的各自作用。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，如促肾上腺皮质激素释放激素（CRH）表达神经元，驱动昼夜能量摄入， 新陈代谢.在分子水平上，我们将使用高通量基因组学方法来阐明 BMAL1调节PVN节律功能的机制。这些目标的圆满实现 将首次确立PVN作为能量摄入节律调节器的先前未知的作用， 体重动态平衡总而言之，对控制消费的神经机制的完整理解 和能量稳态需要开发药理学和行为疗法，以有效地对抗 肥胖