Nutriuretic Peptides, the Renin-Angiotensin System, and Metabolic Risk in Obesity

描述(申请人提供)：肥胖是心血管疾病(CVD)发病率和死亡率的主要原因。肥胖心血管风险的一个基本中介因素是胰岛素抵抗和代谢危险因素(葡萄糖耐量不足、血脂异常和高血压)的发展。然而，肥胖的代谢风险是不同的。RAAS的激活是肥胖的一个关键特征，减肥可能会逆转这一特征。激活的RAAS触发NP的释放，NP是重要的反调节激素。出乎意料的是，在肥胖者中，NP水平比升高时更低，这表明肥胖与“利钠障碍”有关，RAAS和NP途径对葡萄糖代谢和脂肪细胞功能产生重要而相反的影响。此外，药物阻断RAAS与降低糖尿病发病率有关。我们假设肥胖者肾素-血管紧张素-醛固酮系统(RAAS)激活和钠尿肽(NP)下调的失衡导致代谢风险的异质性。我们建议通过获得RAAS(血浆肾素、血管紧张素转换酶、醛固酮)和NP(N末端前B型利钠肽、N末端前心房利钠肽，cGMP)生物标志物的一系列测量来验证我们的假设，并将它们与在大型社区队列(Framingham心脏研究[FHS]第三代和少数OMNI第二代参与者)中对代谢危险因素的纵向跟踪联系起来。我们的具体目标是(1)检查肥胖和纵向体重变化(超过4年)与循环RAAS/NP生物标记物的相关性；(2)将RAAS/NP生物标记物与发展代谢特征的风险联系起来；以及(3)确定RAAS/NP基因的常见遗传变异与生物标记物水平和代谢特征的关系，作为对这些途径的病因学重要性的测试(孟德尔随机化)。FHS第三代和OMNI第二代队列提供了大量(n=4000)单一地点、以社区为基础的年轻人样本，他们心血管疾病患病率较低，但肥胖症和代谢风险因素的患病率较高。该项目的科学产量将通过现有的代谢和炎症标志物数据库(通过其他机制资助)、广泛的遗传资源和大型复制队列来提高。肥胖者有证据表明两种激素途径(肾素-血管紧张素-醛固酮系统，钠尿肽系统)的活性改变，这可能导致他们对高血糖、高胆固醇和高血压等疾病的易感性。对这些途径的生化标记物的评估可以确定肥胖者发生心血管危险因素的风险更高，并可能提出新的治疗靶点。

DESCRIPTION (provided by applicant): Obesity accounts for substantial cardiovascular disease (CVD) morbidity and mortality. A fundamental mediator of CVD risk in obesity is the development of insulin resistance and metabolic risk factors (glucose ntolerance, dyslipidemia, and hypertension). However, metabolic risk in obesity is heterogeneous. Activation of the RAAS is a key feature of obesity that may be reversed by weight loss. An activated RAAS triggers the release of NP, which are important counter-regulatory hormones. Unexpectedly, NP levels are depressed ather than elevated in obese individuals, suggesting that obesity is associated with a "natriuretic handicap," The RAAS and NP pathways exert important and opposing influences on glucose metabolism and adipocyte function. Further, pharmacological RAAS blockade is associated with a reduced incidence of diabetes. We hypothesize that the imbalance of renin-angiotensin-aldosterone system (RAAS) activation and natriuretic peptide (NP) downregulation in obese individuals contributes to heterogeneity in metabolic risk. We propose to test our hypothesis by obtaining serial measures of RAAS (plasma renin, angiotensin converting enzyme, aldosterone) and NP (N-terminal pro-B-type natriuretic peptide, N-terminal pro-atrial natriuretic peptide, cGMP) biomarkers, and relating them to longitudinal tracking of metabolic risk factors in a large, community- based cohort (Framingham Heart Study [FHS] 3rd generation and minority Omni 2nd generation participants). Our specific aims are (1) to examine the associations of obesity and longitudinal weight change (over 4 years) with circulating RAAS/NP biomarkers; (2) to relate RAAS/NP biomarkers to the risk of developing metabolic traits; and (3) to define the relations of common genetic variation in RAAS/NP genes with biomarker levels and metabolic traits, as a test of the etiologic importance of these pathways (Mendelian randomization). The FHS 3rd generation and Omni 2nd generation cohorts provide a large (n=4000), single- site, community-based sample of young adults with low CVD prevalence, but a high prevalence of obesity and metabolic risk factors. The scientific yield of the project will be enhanced by existing databases of metabolic and inflammatory markers funded via other mechanisms, extensive genetic resources, and a large replication cohort. Obese individuals have evidence of altered activity in 2 hormonal pathways (renin-angiotensin-aldosterone system, natriuretic peptide system), which may contribute to their susceptibility to developing conditions such as elevated blood sugar, high cholesterol, and hypertension. Assessment ofbiochemial markers of these pathways may identify obese individuals at higher risk of developing cardiovascular risk factors and may suggest novel therapeutic targets.