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控制，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1亿人 每年花费大约2000亿美元。因此，我们必须找到 在肥胖问题失控之前找到更好的治疗方法。大脑中蕴藏着未开发的潜能 肥胖症治疗的途径。虽然很明显神经机制可以极大地转移能量 内稳态，这些机制已经很少描述到这一点。专门的神经元检测变化 在能量状态。由于大脑消耗了体内几乎四分之一的营养物质， 这对大脑将能量水平保持在正常范围很重要。因此，有未被发现的，或没有 完全被发现的，大脑中维持能量平衡的内置系统。 最近的研究旨在了解大脑中不同细胞组的功能，这些细胞参与了 代谢功能的各个方面。这是最近发现的一个关键领域的情况， 叫做腹内侧下丘脑。我们已经发表了论文，确定了一组细胞， 脑区对于低血糖反调节是必不可少的，这是糖尿病治疗的关键因素。这些细胞 在同一区域与其他对能量平衡至关重要的物质混合在一起， 支出去除以神经肽垂体腺苷酸环化酶激活多肽为中心的 腹内侧下丘脑诱发肥胖。因为腹内侧动脉和 下丘脑与外周器官靶点，这些功能必须通过下游部位控制， 对垂体腺苷酸环化酶激活多肽有反应 在这个建议中，我们的目标是确定在区域中的解剖和细胞靶点， 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 神经元只投射到少数几个地方这些投影尤其与视前核的尾侧分支重叠 这是一个对能源消耗控制至关重要的地区。我们将采用遗传小鼠模型， AAV驱动的功能获得或丧失实验，以测试传递燃料的饮食信号的假设 充分参与下丘脑腹内侧的神经肽和视前区内的作用， 抑制性神经元，含有神经肽的受体。我们将定义饮食信号， 需要下丘脑腹内侧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 通过这些细胞。然后，我们将确定视前区内含有神经肽的抑制细胞 受体及其参与的外周活动通过能量消耗来支持能量平衡。