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）：该项目的目标是评估心利钠肽（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”受体 NPRC 的小鼠会变得瘦弱且代谢亢进，白色脂肪组织库中含有大量棕色脂肪细胞。这种表型被认为是由于 NPRC 缺乏从循环中清除 NP 的能力，因此鸟苷酸环化酶偶联“信号”受体 NPRA 的激活不受限制。患有肥胖和代谢综合征的人的脂肪组织中循环 NP 水平降低，而 NPRC 水平升高；人们怀疑这种情况会进一步导致体重增加和血压升高。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 NPRA 和 NPRC 受体都受到激素环境、饮食和交感神经系统激活的高度调节，因此该项目还将分离 NPRA 和 NPRC 基因的调节区域，以确定负责的基因区域它们显着的转录变化导致 NPRA 与 NPRC 的比率发生变化。纳米粒子从心脏分泌后相对较快地失活。它们不仅被 NPRC 从循环中“清除”，而且还被中性肽链内切酶 (NEP) 快速降解。因此，我们项目的第三个目标将测试一个概念，即修饰含有 Fc 部分的 NP 形式以增加循环半衰期，并降低对 NPRC 的亲和力，这将是长寿命且足够有效的药物，可降低血液压力并增加脂肪氧化。因此，该目标被设计为早期阶段的转化概念验证项目，我们将从中获得可能对药物开发有用的重要知识。通过了解对纳米粒子做出反应以刺激新陈代谢的组织，再加上对这些受体在这些靶组织中如何调节的更好的机制理解以及从早期“治疗”工作中获得的结果，该项目将为以下方面提供重要基础：旨在建立未来的研究工作以及肥胖和高血压的临床方法。