Defining the neurocircuit activated by the VMH to control energy expenditure.

定义由 VMH 激活的神经回路来控制能量消耗。

• 批准号: 10717770
• 负责人: Jonathan Nicholas Flak
• 金额: $ 35.31万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-17 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717770
• 关键词: Ablation; Adipose tissue; Affect; Agonist; Anatomy; Anterior; Area; Body Weight; Body Weight decreased; Brain; Brain Stem; Brain region; Cell Communication; Cells; Communication; Cost of Illness; Country; Data; Development; Diabetes Mellitus; Diet; Eating; Electrophysiology (science); Energy Metabolism; Fasting; Fatty acid glycerol esters; Fiber; GCG gene; Genes; Genetic; Goals; Homeostasis; Hypoglycemia; Hypothalamic structure; Individual; Injections; Leptin; Medial; Mediating; Metabolic; Metabolic Diseases; Midbrain structure; Morbidity - disease rate; Mus; Muscle; Neurons; Neuropeptide Receptor; Neuropeptides; Normal Range; Nutrient; Obesity; Obesity associated disease; Organ; Outcome; Output; Paper; Patients; Peripheral; Persons; Preoptic Areas; Process; Publishing; Research; Role; Signal Transduction; Site; Structure of paraventricular nucleus of thalamus; Structure of terminal stria nuclei of preoptic region; System; Testing; Thermogenesis; Tissues; United States; Weight maintenance regimen; bariatric surgery; cellular targeting; cost; counterregulation; dietary; energy balance; exhaust; experimental study; gamma-Aminobutyric Acid; inhibitory neuron; loss of function; mortality; mouse model; neural circuit; neuromechanism; new therapeutic target; novel; novel therapeutics; obesity treatment; pituitary adenylate cyclase activating polypeptide; receptor; recombinase; response; side effect; weight loss intervention

PROJECT ABSTRACT While body weight is tightly regulated in healthy individuals, obesity results from failed homeostatic mechanisms that protect individuals from metabolic disease. Obesity already plagues approximately 100 million people and costs approximately $200 billion dollars annually in this country. Thus, it is imperative that we find better ways to treat obesity before this problem gets out of control. The brain contains unexplored potential avenues for obesity treatment. While it has been clear that neural mechanisms can dramatically shift energy homeostasis, these mechanisms have been poorly described to this point. Specialized neurons detect changes in energy status. Because the brain exhausts almost a quarter of all nutrients in the body, it is especially important for the brain to keep energy levels in a normal range. Therefore, there are undiscovered, or not completely discovered, built-in systems into the brain that maintain energy homeostasis. Recent studies have aimed to understand the function of distinct sets of cells in the brain involved in individual aspects of metabolic function. This has recently been revealed to be the case for a key area of the brain called the ventromedial hypothalamus. We have published papers that identify a set of cells within this brain area is essential for hypoglycemic counterregulation, a critical factor for diabetes treatment. These cells are intermingled in the same area with others that are essential for energy balance by stimulating energy expenditure. Removing the neuropeptide pituitary adenylate cyclase activating polypeptide centered on the ventromedial hypothalamus induces obesity. Because there are no direct connections from the ventromedial hypothalamus with peripheral organ targets, these functions must be controlled through a downstream site to that responds to pituitary adenylate cyclase activating polypeptide. In this proposal, we aim to identify both the anatomical and the cellular targets in the regions that ventromedial hypothalamus neurons project. Our preliminary data indicate that ventromedial hypothalamus neurons only project to a few sites. These projections particularly overlay with the caudal divisions of the preoptic area, a region critical to energy expenditure control. We will employ genetic mouse models in conjunction with AAV-driven gain or loss of function experiments to test the hypothesis that dietary signals that communicate fuel adequacy to engage the neuropeptide in the ventromedial hypothalamus and action within the preoptic area on neurons that are inhibitory and contain the receptor for the neuropeptide. We will define the dietary signals that require the ventromedial hypothalamus neuropeptide and downstream communication by these cells. We will then determine the downstream regions that requires activation by the neuropeptide receptor and communication by these cells. Then, we will identify the inhibitory cells within the preoptic area that contain the neuropeptide receptor and the peripheral actions they engage to support energy balance through energy expenditure.

项目摘要 虽然健康个体的体重受到严格调节，但肥胖是由于体内平衡失败造成的 保护个体免受代谢疾病的机制。肥胖已经困扰着大约一亿人 这个国家每年的人力和成本约为 2000 亿美元。因此，我们迫切需要找到 在这个问题失控之前，找到更好的方法来治疗肥胖。大脑蕴藏着未开发的潜力 肥胖症治疗的途径。虽然很明显神经机制可以显着转移能量 稳态，到目前为止，这些机制的描述还很少。专门的神经元检测变化 处于能量状态。由于大脑几乎耗尽了身体所有营养物质的四分之一，因此尤其如此 对于大脑将能量水平保持在正常范围内很重要。所以，还有未被发现的，或者说没有 完全被发现的、大脑中维持能量稳态的内置系统。 最近的研究旨在了解大脑中参与的不同细胞组的功能 代谢功能的各个方面。最近有消息称，该项目的一个关键领域就是这种情况。 大脑称为下丘脑腹内侧。我们发表的论文鉴定了其中的一组细胞 大脑区域对于低血糖反调节至关重要，而低血糖反调节是糖尿病治疗的关键因素。这些细胞 与其他区域混合在一起，通过刺激能量来实现能量平衡 支出。去除以神经肽为中心的垂体腺苷酸环化酶激活多肽 下丘脑腹内侧区诱发肥胖。因为腹内侧没有直接连接 下丘脑具有周围器官目标，这些功能必须通过下游位点控制 响应垂体腺苷酸环化酶激活多肽。 在本提案中，我们的目标是确定以下区域的解剖和细胞目标： 下丘脑腹内侧神经元投射。我们的初步数据表明，下丘脑腹内侧 神经元仅投射到少数部位。这些投影特别与视前区的尾部部分重叠 区域，对能源支出控制至关重要的区域。我们将结合使用遗传小鼠模型 AAV 驱动的功能获得或丧失实验来检验饮食信号传递能量的假设 足以使神经肽参与下丘脑腹内侧并在视前区发挥作用 具有抑制性并含有神经肽受体的神经元。我们将定义饮食信号 需要腹内侧下丘脑神经肽和这些细胞的下游通讯。我们将 然后确定需要神经肽受体激活和通讯的下游区域 由这些细胞。然后，我们将识别视前区内含有神经肽的抑制细胞 受体及其外围活动通过能量消耗支持能量平衡。