PACAP - leptin interaction in the hypothalamic ventromedial nuclei in the regulation of energy homeostasis

PACAP-瘦素在下丘脑腹内侧核中相互作用调节能量稳态

• 批准号: 10063218
• 负责人: SuJean Choi
• 金额: $ 1.3万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063218
• 关键词: Address; Adipose tissue; American; Anatomy; Appetite Stimulants; Behavioral; Body Weight; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cell Nucleus; Cells; Cessation of life; Chronic; Clinical; Complex; Data; Dependence; Development; Diet; Disease; Elements; Energy Intake; Energy Metabolism; Feeding behaviors; Gene Activation; Health; Homeostasis; Hormones; Hypertension; Hypothalamic structure; Impairment; Individual; Investigation; Lead; Leptin; Link; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Modeling; Neurobiology; Neurons; Neuropeptides; Obesity; Obesity Epidemic; Organ; Outcome; Overweight; Pathologic; Pattern; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Population; Property; Pump; Receptor Activation; Receptor Signaling; Regulation; Research; Research Personnel; STAT3 gene; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Stroke; System; Therapeutic; Treatment Efficacy; United States; Weight Gain; Work; diabetes risk; energy balance; experience; experimental study; feeding; leptin receptor; neural network; new therapeutic target; novel; peptide hormone; pituitary adenylate cyclase activating polypeptide; receptor; relating to nervous system; success; tool; undergraduate student; ventromedial hypothalamic nucleus

Project Summary/Abstract The impact of the obesity epidemic in the US has been estimated to endanger the health of up to 30% of Americans by increasing the risk of diabetes, hypertension, stroke, and cancer as well as leading to 300,000 deaths annually. In order to lessen the negative impact of obesity, there is a need to better understand the neurobiology of feeding and metabolism in a manner that could contribute to the development of effective therapeutics. Attempts to understand the neural basis of feeding and metabolism often involve the study of individual neuropeptides that alter caloric intake and/or energy expenditure. Anatomical studies have implicated subregions of the hypothalamus as sites of action for several dozen peptide regulators of feeding behavior and body weight. Specifically, the ventromedial nuclei of the hypothalamus (VMN) exert powerful control over feeding and metabolism through a broad array of both central and peripheral signaling molecules. For example, leptin, a well- studied peripheral signal produces hypophagia when administered into the VMN. Centrally, the actions of the VMN on energy homeostasis are also dependent on the activity of neural inputs synthesized and released by other brain regions such as the neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP), which promotes energy expenditure and decreases feeding behavior. Thus, neurons in the VMN likely integrate both neural and peripheral signals in order to regulate energy homeostasis. Preliminary data in this proposal support the hypothesis that leptin and PACAP interact in the VMN by regulating shared intracellular signaling pathways that lead to hypophagia. This is not surprising given the common and parallel features between PACAP and leptin in terms of anatomy, behavioral and metabolic outcomes, gene activation patterns, and functional dependency. This proposal examines several points of convergence among the intracellular signals produced by leptin and PACAP including the JAK-STAT signaling cascade and BDNF expression. Moreover, PACAP and leptin are ideal candidates to study the functional interactions between a tonically peripheral signal and a synaptically released neuropeptide that together could alter the activity of a broad neural network responsible for feeding behavior and energy homeostasis. In the hypothalamic VMN, we will examine the intracellular signaling links between PACAP and leptin (aim 1), and the functional relationship between PACAP and leptin under chronic conditions of leptin receptor dysregulation with obesity, hyperleptinemia without obesity, and diet induced obesity (aim 2).

项目总结/摘要 据估计，美国肥胖流行病的影响将危及多达 30%的美国人患糖尿病、高血压、中风和癌症的风险增加， 导致每年30万人死亡为了减少肥胖的负面影响，需要 为了更好地了解进食和新陈代谢的神经生物学，从而有助于 开发有效的治疗方法。试图了解进食的神经基础， 代谢通常涉及改变热量摄入和/或能量的单个神经肽的研究 支出解剖学研究暗示下丘脑的亚区域是作用部位 几十种肽调节剂的喂养行为和体重。具体而言是 下丘脑腹内侧核（VMN）对摄食和代谢具有强大的控制作用 通过一系列的中枢和外周信号分子。例如，瘦素，一种很好的- 所研究的外周信号在被施用到VMN中时产生食欲减退。在中央， VMN对能量稳态的作用也依赖于神经输入的活动 由其他脑区合成和释放，如神经肽，垂体腺苷酸 环化酶激活多肽（PACAP），促进能量消耗，减少摄食 行为因此，VMN中的神经元可能整合神经和外周信号，以便 调节能量稳态。 本研究的初步数据支持瘦素和PACAP在VMN中相互作用的假设 通过调节共同的细胞内信号通路导致食欲减退。这并不奇怪 考虑到PACAP和瘦素在解剖学、行为学和免疫学方面的共同和平行特征， 代谢结果、基因激活模式和功能依赖性。这项建议 研究了瘦素产生的细胞内信号之间的几个会聚点， PACAP包括JAK-STAT信号级联和BDNF表达。此外，PACAP和 瘦素是研究紧张性外周信号之间的功能相互作用的理想候选物， 和一种突触释放的神经肽，它们一起可以改变一种广泛的神经系统的活动， 负责进食行为和能量稳态的网络。在下丘脑VMN中，我们将 检查PACAP和瘦素之间的细胞内信号联系（目的1），以及功能性 慢性瘦素受体失调状态下PACAP与瘦素的关系 肥胖、无肥胖的高瘦素血症和饮食诱导的肥胖（AIM 2）。