Natriuretic peptide receptors, adipose browning and energy expenditure

利钠肽受体、脂肪褐变和能量消耗

基本信息

批准号：
8768157
负责人：
SHEILA COLLINS
金额：
$ 42.41万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8768157
关键词：
Adipocytes Adipose tissue Adrenergic Receptor Adult Aerobic Affinity Agonist Alleles Animal Model Atrial Natriuretic Factor Biogenesis Biological Biological Assay Blood Blood Circulation Blood Pressure Body Weight decreased Body fat Brown Fat Burn injury Calories Cardiac Cardiac Output Cells Chimeric Proteins Clinical Clinical Research Clinical Trials Clothing Comorbidity Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP-Dependent Protein Kinases Development Diet Energy Metabolism Exercise Exhibits Fasting Fatty Acids Fatty acid glycerol esters Figs - dietary Foundations Future Genes Genetic Genetic Transcription Glucose Goals Guanylate Cyclase Half-Life Heart Heating Hormonal Hormones Housing Human Hypertension Hypotension In Vitro Incidence Individual Kidney Knowledge Lead Life Location MAP Kinase Gene MAPK14 gene Metabolic Metabolic syndrome Metabolism Mitochondria Molecular Mus Muscle Myocardium Natriuretic Peptides Neprilysin Non-Insulin-Dependent Diabetes Mellitus Nucleic Acid Regulatory Sequences Nutritional Obesity PPAR gamma Pathway interactions Pattern Peptide Receptor Pharmacologic Substance Phenotype Physiological Physiology Production Proteins Protons Receptor Signaling Regulation Relative (related person)Reporter Genes Respiration Role Shivering Signal Transduction Skeletal Muscle Staging Sympathetic Nervous System Testing Therapeutic Tissues Transcriptional Regulation Triglycerides Weight Gain Work atrial natriuretic factor receptor A base cGMP production cell type design fatty acid oxidation improved in vivo insulin sensitivity lipid metabolism mitogen-activated protein kinase p38 mouse model novel oxidation peptide B pre-clinical programs public health relevance receptor receptor expression response skeletal uncoupling protein 1

项目摘要

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.

描述（由申请人提供）：该项目的目的是评估心纳二肽（NP）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“清除率”受体NPRC的小鼠成长为瘦和超级代谢，在白色脂肪组织库中有大量的棕色脂肪细胞。据信这种表型是由于NPRC循环缺乏NP清除率，因此鸟类环偶联偶联的“信号”受体NPRA毫无限制地激活。患有肥胖和代谢综合征的人的脂肪组织中循环NP的水平降低，NPRC水平升高。并且怀疑这种情况有助于进一步增加体重升高血压。在这个项目中，我们将生成独特的动物模型，其中NPRC从脂肪组织和骨骼肌中选择性删除，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均受响应激素环境，饮食和激活的交感神经系统的高度调节，因此该项目还将隔离NPRA和NPRC基因的调节区域，以确定基因区域的重大转录变化区域，从而导致NPRA的变化比率变化。 NP从内心分泌后相对较快地灭活。它们不仅被NPRC从循环中“清除”，而且还通过中性内肽酶（NEP）迅速降解。因此，我们项目的第三个目标将测试一个概念，该概念修改了含有FC部分的NP形式，以增加循环半衰期的循环，以及对NPRC的亲和力的降低，将是长期寿命和足够有效的剂量，以降低血压和增加脂肪氧化。因此，该目标被设计为一个早期的转化概念验证项目，我们将从该项目中获取重要的知识，这些知识可能在药物开发中有用。通过了解对NP响应以刺激新陈代谢的组织，再加上对这些受体如何调节这些受体在这些目标组织中的调节以及从早期的“治疗性”工作中获得的结果的理解，该项目将共同提供一个重要的基础，以建立一个重要的基础，以建立未来的研究工作以及对肥胖和高度的临床方法。