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

项目摘要/摘要 据估计，美国肥胖症流行的影响将危及多达 30%的美国人通过增加患糖尿病、高血压、中风和癌症的风险以及 导致每年30万人死亡。为了减轻肥胖的负面影响，有必要 为了更好地了解摄食和新陈代谢的神经生物学，有助于 有效疗法的发展。试图理解进食和呼吸的神经基础 新陈代谢通常涉及对改变卡路里摄入量和/或能量的个别神经肽的研究。 支出。解剖学研究表明，下丘脑的亚区是活动的部位。 用来调节摄食行为和体重的几十种多肽。具体地说， 下丘脑腹内侧核(VMN)对摄食和代谢具有强大的控制作用 通过一系列广泛的中枢和外周信号分子。例如，瘦素，一口井- 学习的外周信号在给VMN注射时会产生吞噬功能减退。从中央来看， VMN对能量稳态的作用也依赖于神经输入的活动 由其他大脑区域合成和释放，如神经肽、脑垂体腺苷 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 调节能量动态平衡。 该方案中的初步数据支持瘦素和PACAP在VMN中相互作用的假设 通过调节共同的细胞内信号通路导致低噬。这并不令人惊讶 鉴于PACAP和瘦素在解剖、行为和行为方面的共同和相似特征 代谢结果、基因激活模式和功能依赖。这项建议 检查瘦素和瘦素产生的细胞内信号之间的几个趋同点 PACAP包括JAK-STAT信号级联和BDNF的表达。此外，PACAP和 瘦素是研究强直外周信号之间功能相互作用的理想候选者 以及一种突触释放的神经肽，它们一起可以改变广泛神经的活动 负责摄食行为和能量平衡的网络。在下丘脑VMN，我们将 研究PACAP和瘦素之间的细胞内信号联系(目标1)，以及功能 慢性瘦素受体失调与PACAP和瘦素的关系 肥胖、无肥胖的高瘦素血症和饮食诱导的肥胖(目标2)。

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).