Natriuretic peptide and cGMP signaling in adipose tissue and energy metabolism

脂肪组织和能量代谢中的利钠肽和 cGMP 信号传导

• 批准号: 10609907
• 负责人: SHEILA COLLINS
• 金额: $ 50.03万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609907
• 关键词: Adipocytes; Adipose tissue; Adult; Agonist; Atrial Natriuretic Factor; Binding; Body Composition; Body Temperature; Body Weight; Body fat; Brain natriuretic peptide; Brown Fat; Calories; Cardiac; Cardiometabolic Disease; Cardiovascular Diseases; Catecholamines; Cells; Chronic; Circulation; Clinical Research; Consumption; Critical Pathways; Cyclic AMP; Cyclic GMP; Data; Denervation; Disease; Elements; Energy Intake; Energy Metabolism; Enzymes; Epidemic; Fasting; Fatty Acids; Fatty Liver; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glucose; Goals; Health; Healthcare; High Fat Diet; Histology; Homeostasis; Human; Incidence; Income; Individual; Infusion procedures; Insulin; Insulin Resistance; Knockout Mice; Knowledge; Ligands; MME gene; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Molecular; Mus; Natriuretic Peptides; Nature; Neprilysin; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Obesity; Operative Surgical Procedures; Pattern; Peptide Hydrolases; Peptide Receptor; Pharmaceutical Preparations; Physiological; Plasma; Process; Production; Productivity; Proteins; Protons; Publishing; Quality of life; Risk Reduction; Role; Signal Pathway; Signal Transduction; Sympathetic Nervous System; Syndrome; System; Temperature; Testing; Thermogenesis; Thinness; Tissues; Transcriptional Regulation; Triglycerides; Work; beta-adrenergic receptor; cGMP production; cardiometabolism; cold temperature; economic impact; effective therapy; genome-wide; glucose tolerance; improved; in vivo; insulin sensitivity; insulin tolerance; liver inflammation; mouse model; novel; obese person; peptide analog; phosphoric diester hydrolase; prevent; programs; protein expression; receptor; receptor expression; recruit; response; saluretic; uncoupling protein 1; uptake

PROJECT SUMMARY The epidemic of cardiometabolic disease occurring throughout the world is taking a heavy toll on individuals’ quality of life, along with a huge economic impact Excess caloric intake leading to obesity is a major driver of the cardiometabolic syndrome. Brown adipose tissue (BAT) evolved in homeotherms as a mean to maintain body temperature by generating heat from stored calories. Brown adipocytes are highly enriched in mitochondria and express a unique protein called uncoupling protein-1 (UCP1). UCP1 ‘uncouples’ the mitochondrial proton gradient from ATP production, thus avidly consuming glucose and fatty acids with the result being net energy expenditure. Active brown fat is present in adult humans and its amount is significantly correlated with reduced body fat and circulating triglycerides, greater insulin sensitivity, and lowered incidence of Type II diabetes. Increasing brown adipocyte amount and activity could reduce the risk of cardiometabolic disease. The sympathetic nervous system (SNS)-derived catecholamine norepinephrine, which act through β-adrenergic receptors and cAMP, is a well-established activator of BAT and the recruitment of UCP1-positive cells in white adipose tissue (WAT) depots (a process termed ‘browning’ or ‘beiging’). We have shown in prior work that the cardiac hormones atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) also stimulate a similar ‘browning’ program in mouse and human adipocytes, and protect against obesity-associated insulin resistance, hepatic steatosis and inflammation. This suggests that increasing NP signaling in adipose tissues is metabolically beneficial. NP activation of NP receptor A (NPRA) leads to cGMP production, while the NP ‘clearance receptor’ NPRC removes NPs from circulation, and the ratio of NPRA to NPRC determines NP signaling capacity. Clinical studies show that compared to lean individuals, obese individuals have lower circulating NP level, increased NPRC level in adipose tissue, and blunted lipolytic responses to NPs. We observed similar patterns of receptor expression and physiological responses in mice. It has been postulated that higher adipose NPRC levels increases NP clearance, thus reducing NP availability in the circulation and efficacy in target tissues, resulting in a so-called ‘natriuretic handicap’. On the other hand, conditions such as fasting and cold temperature exposure reduce the level of NPRC expression, resulting in an increased NPRA/NPRC ratio and thus NP/cGMP signaling. Our studies with mouse models further support these observations. We also find that the expression of other components of the NP signaling system, such as phosphodiesterase-9 and the peptidase neprilysin are also decreased in response to cold and βAR agonists The overall objective of this project is to: define the transcriptional regulatory mechanisms of the Nprc, Pde9 and Mme genes in human and mouse adipocytes; determine whether increased levels of NPRC in obesity serves as a ‘sink’ to remove NPs from circulation, thus creating the ‘natriuretic handicap’, and test the effects of selective NP ligands to modulate insulin sensitivity.

项目摘要 心脏代谢性疾病的流行在全世界范围内发生， 生活质量，沿着巨大的经济影响过量的热量摄入导致肥胖是一个主要的驱动力， 心脏代谢综合征 棕色脂肪组织（BAT）在恒温动物中进化，通过产生 储存的热量。棕色脂肪细胞高度富集线粒体并表达一种独特的蛋白质 称为解偶联蛋白-1（UCP 1）。UCP 1将线粒体质子梯度与ATP产生“解偶联”， 从而贪婪地消耗葡萄糖和脂肪酸，结果是净能量消耗。活性棕色脂肪是 存在于成年人中，并且其量与减少的体脂和循环显著相关。 甘油三酯，更高的胰岛素敏感性和降低II型糖尿病的发病率。增加棕色脂肪细胞 量和活动可以降低心脏代谢疾病的风险。 交感神经系统（SNS）来源的儿茶酚胺去甲肾上腺素，通过β-肾上腺素能神经递质发挥作用。 受体和cAMP，是BAT和白色中UCP 1阳性细胞募集的公认激活剂 脂肪组织（WAT）贮库（称为“布朗宁”或“褐变”的过程）。我们在先前的工作中已经表明， 心脏激素心房利钠肽（ANP）和B型利钠肽（BNP）也刺激类似的 “布朗宁”程序，并防止肥胖相关的胰岛素抵抗， 肝脂肪变性和炎症。这表明脂肪组织中NP信号的增加是代谢性的。 有利于NP受体A（NPRA）的NP活化导致cGMP产生，而NP“清除受体” NPRC从循环中去除NP，并且NPRA与NPRC的比率决定NP信号传导能力。临床 研究表明，与瘦个体相比，肥胖个体具有较低的循环NP水平， 脂肪组织中的NPRC水平，以及对NP的脂解反应减弱。我们观察到类似的受体模式， 表达和生理反应。据推测，较高的脂肪NPRC水平 增加NP清除率，从而降低NP在循环中的可用性和在靶组织中的功效， 所谓的“利钠障碍”另一方面，禁食和低温暴露等条件 降低NPRC表达水平，导致NPRA/NPRC比率增加，从而导致NP/cGMP信号传导。 我们对小鼠模型的研究进一步支持了这些观察结果。我们还发现，表达其他 NP信号传导系统的组分，如磷酸二酯酶-9和肽酶脑啡肽酶也是 本项目的总体目标是： 人和小鼠脂肪细胞中Nprc、Pde 9和Mme基因的转录调控机制; 确定肥胖症中NPRC水平的增加是否作为从循环中去除NPs的“水槽”， 产生“利钠障碍”，并测试选择性NP配体调节胰岛素敏感性的作用。