Natriuretic peptide and cGMP signaling in adipose tissue and energy metabolism

项目总结 心脏代谢性疾病在世界各地的流行正在给个人造成沉重的损失 生活质量，以及巨大的经济影响，过量摄入卡路里导致肥胖是导致肥胖的主要原因 心脏代谢综合征。 棕色脂肪组织(BAT)是在恒温动物中进化而来的，通过产生 来自储存的卡路里的热量。棕色脂肪细胞高度富含线粒体，并表达一种独特的蛋白质。 称为解偶联蛋白-1(UCP1)。UCP1将线粒体的质子梯度与ATP的产生“解偶联”， 因此，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 在成人中存在，其含量与体内脂肪减少和循环显著相关 甘油三酯、更高的胰岛素敏感性和更低的II型糖尿病发病率。棕色脂肪细胞增多 运动量和活动量可以降低心脏代谢性疾病的风险。 交感神经系统来源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，是一种公认的BAT激活剂和UCP1阳性细胞在白色体内的募集 脂肪组织(WAT)堆积(这一过程被称为“褐变”或“褐变”)。我们在以前的工作中已经表明， 心脏激素心钠素(ANP)和B型利钠肽(BNP)也刺激类似的 在小鼠和人类脂肪细胞中的“棕色”程序，并防止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信号的增加是新陈代谢的 有益的。NP受体A(NPRA)的NP激活导致cGMP的产生，而NP的“清除受体” NPRC将NP从循环中移除，NPRA与NPRC的比例决定了NP的信号容量。临床 研究表明，与瘦肉者相比，肥胖者血液中NP水平较低，而较高 脂肪组织中的NPRC水平，以及对NPs的钝化脂解反应。我们观察到了类似的受体模式 在小鼠体内的表达和生理反应。据推测，较高的脂肪NPRC水平 增加NP的清除，从而降低NP在循环中的可用性和在靶组织中的有效性，从而导致 患有所谓的“利钠障碍”。另一方面，禁食和寒冷温度暴露等条件 降低NPRC的表达水平，导致NPRA/NPRC比值增加，从而导致NP/cGMP信号转导。 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，其他人的表达 NP信号系统的组成部分，如磷酸二酯酶-9和肽酶neprilysin也是 对COLD和β受体激动剂的反应减少本项目的总体目标是：定义 NPRC、Pde9和Mme基因在人和小鼠脂肪细胞中的转录调控机制； 确定肥胖症患者NPRC水平的增加是否起到了将NPs从血液循环中清除的作用，因此 制造“利钠障碍”，并测试选择性NP配体调节胰岛素敏感性的效果。

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.