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.

项目概要 世界范围内流行的心脏代谢疾病正在对个人的健康造成严重损害 生活质量以及巨大的经济影响导致肥胖的热量摄入过多是导致肥胖的一个主要驱动因素 心脏代谢综合征。 棕色脂肪组织（BAT）在恒温动物中进化而来，通过产生热量来维持体温。 棕色脂肪细胞富含线粒体并表达一种独特的蛋白质。 称为解偶联蛋白-1 (UCP1)，将线粒体质子梯度与 ATP 生成“解偶联”， 因此，大量消耗葡萄糖和脂肪酸，结果是活性棕色脂肪的净能量消耗。 存在于成年人中，其数量与体内脂肪和循环的减少显着相关 甘油三酯，更高的胰岛素敏感性，并降低 II 型糖尿病的发生率 增加棕色脂肪细胞。 数量和活动可以降低心脏代谢疾病的风险。 交感神经系统 (SNS) 衍生的儿茶酚胺去甲肾上腺素，通过 β-肾上腺素能发挥作用 受体和 cAMP，是一种成熟的 BAT 激活剂，可招募白细胞中的 UCP1 阳性细胞 脂肪组织（WAT）库（称为“褐变”或“米色”的过程）。 强心激素心房钠尿肽（ANP）和B型钠尿肽（BNP）也能刺激类似的作用。 小鼠和人类脂肪细胞中的“褐变”程序，并防止与肥胖相关的胰岛素抵抗， 肝脏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。 NP 受体 A (NPRA) 的 NP 激活会导致 cGMP 产生，而 NP“清除受体” NPRC 将 NP 从循环中去除，NPRA 与 NPRC 的比率决定了 NP 的临床信号传导能力。 研究表明，与瘦人相比，肥胖人的循环 NP 水平较低，增加 我们观察到脂肪组织中的 NPRC 水平以及对 NP 的脂肪分解反应减弱。 据推测，小鼠中脂肪 NPRC 水平较高。 增加 NP 清除率，从而降低 NP 在循环中的可用性和靶组织中的功效，从而导致 另一方面，在所谓的“尿钠排泄障碍”中，禁食和寒冷的温度暴露等情况。 降低 NPRC 表达水平，导致 NPRA/NPRC 比率增加，从而增加 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，我们还发现其他的表达。 NP 信号系统的成分，如磷酸二酯酶 9 和肽酶脑啡肽酶也 对寒冷和 βAR 激动剂的反应减少 该项目的总体目标是： 人和小鼠脂肪细胞中 Nprc、Pde9 和 Mme 基因的转录调控机制； 确定肥胖中 NPRC 水平的增加是否作为“水槽”将 NP 从循环中去除，从而 创造“钠尿障碍”，并测试选择性 NP 配体调节胰岛素敏感性的效果。