Natriuretic peptide receptors, adipose browning and energy expenditure

描述（由申请人提供）：本项目的目的是评估心脏利钠肽（NPs）对脂肪代谢和能量消耗的代谢作用。我们描述的研究表明，缺乏NP“清除”受体（NPRC）的小鼠长得很瘦，代谢旺盛，在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在循环中缺乏NP清除，因此不受限制地激活了胍基环化酶偶联的“信号传导”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导致体重增加、血压升高。在这个项目中，我们将生成独特的动物模型，其中NPRC被选择性地从脂肪组织和骨骼肌中删除，以确定这些组织对NPRC-/-小鼠能量消耗的相对贡献。由于受体NPRA和NPRC都受到激素环境、饮食和交感神经系统激活的高度调控，因此该项目还将分离NPRA和NPRC基因的调控区域，以确定导致NPRA与NPRC比例改变的显著转录变化的基因区域。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）迅速降解。因此，我们项目的第三个目标将测试一个概念，即含有Fc片段的修饰形式的NPs可以增加循环半衰期，同时降低对NPRC的亲和力，这将是长期有效的，足以降低血压和增加脂肪氧化的有效药物。因此，这一目标被设计为早期阶段，转化概念验证项目，从中我们将获得可能对药物开发有用的重要知识。通过了解对NPs有反应的组织来刺激新陈代谢，再加上对这些受体在这些靶组织中是如何调节的更好的机制理解，以及从早期“治疗”努力中获得的结果，该项目将为建立未来的调查工作以及肥胖和高血压的临床方法提供重要的基础。

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.