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: 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
• 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' 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

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.

室室下丘脑在喂养和代谢的节奏调节中的作用 仅在美国，肥胖就达到了史诗般的比例，超过7000万成年人肥胖。尽管令人震惊 这种全球流行病的增长，当前的肥胖症治疗疗法在功效上受到限制。几个世纪以来， 过度消费已经是肥胖发病机理的明显罪魁祸首。但是，肥胖的根本原因 是一个多方面的生物学问题，尚未完全理解。最近的研究表明 整个身体的内在生物钟对于调节喂养和体重至关重要 稳态。大规模的流行病学研究对班次工人表明自然昼夜节律的破坏 模式使人屈服于肥胖。对饮食诱发肥胖（DIO）啮齿动物模型的其他研究 在高脂饮食喂养上显示昼夜喂养和运动活性的初始钝化，表明双向 肥胖与昼夜节律之间的关系。最终，轮班工人和DIO小鼠都有 跨外围组织和中央时钟跨越了广泛的对同步。这种结耦表明身体 - 宽的时钟可能与肥胖的发病机理有关。该提议以 了解驱动节奏能量摄入和支出的昼夜节律机制。更具体地说， 该提案的重点是下丘脑的旁脑核（PVN），其重要功能是 饱腹感和代谢的整合器和调节器。一旦被认为仅作为外围时钟的功能 主时钟（Sustrachiasmatic核[SCN]），PVN已被确定为具有自己的内在时钟。 电生理记录揭示了抑制性GABA能神经元的活性的昼夜波动 PVN的营养信息。这些波动似乎是由BMAL1驱动的（大脑和肌肉arnt- 类似1），这是维持各种细胞中稳健节奏的必不可少的转录因子 身体。重要的是，我们的初步数据表明，PVN中BMAL1函数的诱导性丧失 对应于小鼠心律不齐的摄入量。该建议将调查BMAL1驱动的作用 PVN中的机制是控制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 该提案进一步表征了PVN节奏的互动，该提案还将解决哪个PVN神经元 亚型，例如表达激素（CRH）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照亮分子 BMAL1调节PVN节奏功能的机械。这些目标的成功完成 将首次确立PVN作为能量摄入的节奏调节剂的先前未知角色 体重体内稳态。总的来说，对消费的神经机制有完整的理解 需要能量稳态来开发药理和行为疗法以有效作战 肥胖。