Natriuretic peptide receptors, adipose browning and energy expenditure

描述(申请人提供)：本项目的目标是评估心钠素(NPs)对脂肪代谢和能量消耗的代谢影响。我们描述的研究表明，缺乏NP‘Clearance’受体NPRC的小鼠会变得瘦弱和高度代谢，白色脂肪组织库中有大量的棕色脂肪细胞。这种表型被认为是由于NPRC没有将NP从循环中清除出去，从而不受限制地激活了鸟苷酸环化酶偶联的信号受体NPRA。肥胖和代谢综合征患者的脂肪组织中循环NPs水平降低，NPRC水平升高；人们怀疑这种情况会进一步增加体重增加的倾向，导致血压升高。在这个项目中，我们将建立独特的动物模型，其中有选择地从脂肪组织和骨骼肌中删除NPRC，以确定这些组织对NPRC-/-小鼠能量消耗的相对贡献。由于NPRA和NPRC受体都受激素环境、饮食和交感神经系统激活的高度调控，本项目还将分离NPRA和NPRC基因的调节区，以确定导致NPRA和NPRC显著转录变化的基因区域，这些区域导致NPRA和NPRC的比例改变。NPs从心脏分泌出来后相对较快地失活。它们不仅被NPRC从循环中清除，而且还被中性内肽酶(NEP)非常迅速地降解。因此，我们项目的第三个目标将测试这样一个概念，即含有FC部分的修饰形式的NPs可以延长循环半衰期，并降低与NPRC的亲和力，将是足够有效的降压和增加脂肪氧化的药物。因此，这个目标被设计为一个早期阶段的翻译概念验证项目，从这个项目中我们将获得可能在制药开发中有用的重要知识。通过了解对NPs做出反应以刺激新陈代谢的组织，再加上更好地了解这些受体在这些靶组织中是如何调节的，以及从早期的“治疗”努力中获得的结果，这个项目将提供一个重要的基础，在此基础上建立未来的研究工作以及肥胖和高血压的临床方法。

DESCRIPTION (provided by applicant): The goal of this project is to assess the metabolic effects of cardiac natriuretic peptides (NPs) on fat metabolism and energy expenditure. We described studies showing that mice lacking the NP 'clearance' receptor, NPRC, grow to be lean and hypermetabolic, with significant amounts of brown adipocytes within white adipose tissue depots. This phenotype is believed to be due to the lack of NP clearance from the circulation by NPRC and consequently unrestrained activation of the guanylyl cyclase-coupled 'signaling' receptor, NPRA. Humans with obesity and metabolic syndrome have reduced levels of circulating NPs and increased levels of NPRC in their adipose tissue; and it is suspected that this situation contributes to a further propensity to gain weight elevated blood pressure. In this project we will generate unique animal models in which the NPRC is selectively deleted from adipose tissue and skeletal muscle, to determine the relative contributions of these tissues to the energy expenditure of the NPRC-/- mouse. Since both receptors NPRA and NPRC are highly regulated in response to hormonal milieu, diet and activation of the sympathetic nervous system, this project will also isolate regulatory regions of the NPRA and NPRC genes in order to determine the regions of the gene that are responsible for their significant transcriptional changes that lead to altered ratios of NPRA to NPRC. NPs are inactivated relatively quickly after their secretion from the heart. They are not only 'cleared' from circulation by NPRC, but they are also degraded very quickly by neutral endopeptidase (NEP). Therefore, the third goal of our project will test a concept that modified forms of NPs containing an Fc moiety to increase circulating half-life, as well as a decreased affinity for NPRC, will be long-lived and sufficientl potent agents to both lower blood pressure and increase fat oxidation. As such, this aim is designed as an early stage, translational proof-of-concept project, from which we will gain important knowledge that may be useful in pharmaceutical development. By understanding the tissues that respond to NPs to stimulate metabolism, coupled with a better mechanistic understanding of how these receptors are regulated in these target tissues and results obtained from an early-stage 'therapeutic' effort, together this project will provide an important foundatio upon which to build future investigative work as well as clinical approaches to obesity and hypertension.