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: 9432755
• 负责人: SuJean Choi
• 金额: $ 41.7万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9432755
• 关键词: Address; Adipose tissue; American; Anatomy; Appetite Stimulants; Behavioral; Biological Neural Networks; Body Weight; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cell Nucleus; Cells; Cessation of life; Chronic; Clinical; Complex; Data; Dependency; Development; Diet; Disease; Elements; Energy Intake; Energy Metabolism; Epidemic; 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; 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; 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).

项目摘要/摘要 据估计，肥胖流行的影响危害到美国的健康 30％的美国人通过增加糖尿病，高血压，中风和癌症的风险以及 每年导致30万人死亡。为了减少肥胖的负面影响，有必要 更好地理解喂养和代谢的神经生物学，以可能有助于 有效治疗学的发展。试图了解喂养的神经基础 代谢通常涉及对改变热量摄入和/或能量的单个神经肽的研究 支出。解剖学研究已将下丘脑的子区域视为作用部位 对于喂养行为和体重的几十个肽调节剂。具体来说， 下丘脑（VMN）的腹侧核对喂养和代谢产生强大的控制 通过中央和外围信号分子的广泛阵列。例如，瘦素，一个很好的 研究中的周围信号会产生下降症。中心， VMN对能量稳态的作用也取决于神经输入的活性 由其他大脑区域（例如神经肽，垂体腺苷）合成并释放 循环酶激活多肽（PACAP），可促进能量消耗并减少进食 行为。因此，VMN中的神经元可能会整合神经和周围信号，以便 调节能量稳态。 本提案中的初步数据支持瘦素和PACAP在VMN中相互作用的假设 通过调节导致下降的共享细胞内信号传导途径。这不足为奇 考虑到PACAP和瘦素之间的共同和平行特征，就解剖学而言，行为 以及代谢结果，基因激活模式和功能依赖性。这个建议 检查了瘦素和 PACAP在内，包括JAK-Stat信号级联和BDNF表达。而且，PACAP和 瘦素是研究音调外围信号之间功能相互作用的理想候选者 和突触释放的神经肽可以一起改变宽神经的活性 负责喂养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传导联系（AIM 1）和功能 在瘦素受体失调的慢性条件下，PACAP与瘦素之间的关系与 肥胖症，无肥胖症的高稀释血症和饮食诱发肥胖症（AIM 2）。