Atrial Natriuretic Peptide and Regulation of Cardiometabolic Health: A Genotype-Guided Human Physiological Study

项目摘要 在美国，心脏代谢疾病的负担正在增加。心房利钠肽（ANP） 激素有助于调节葡萄糖利用、能量稳态，是一个主要决定因素 心脏代谢健康我们已经证明了ANP基因（rs 5068）中的一种常见遗传变异， 与更高的ANP水平和更有利的心脏代谢特征相关。我们还确定 microRNA-425（miR-425）减少ANP的产生。有利的遗传变异（rs 5068） 阻止miR-425的结合并确保足够的ANP产生。因此，miR-425仅在 ANP基因型低者，即，没有rs 5068基因变异的人。我们还证明 口服葡萄糖挑战降低ANP水平，而运动挑战增加ANP水平。 然而，ANP基因型对ANP对葡萄糖负荷和运动的反应的影响 挑战之前没有被审查过。我们已经证明miR-425是葡萄糖响应性的， 并可调节ANP对代谢紊乱的反应。miR-425对葡萄糖的反应 挑战、运动挑战及其与能量消耗（EE）的关系在人类中尚不清楚。 我们假设，具有低ANP基因型的个体将（1）通过以下方式对ANP有更大的抑制： 葡萄糖挑战，（2）具有较低的静息和运动EE，和（3）证明 miR-425与代谢紊乱（葡萄糖激发和运动激发）的关系。我们建议进行一项 基因型指导的研究，通过在高和低ANP个体中进行详细的代谢分析 基因型在我们的目标1中，我们将招募200名健康成人（50名具有高ANP基因型，150名具有低ANP基因型）， ANP基因型），我们将评估MRproANP对葡萄糖激发反应的差异， 基因型组。我们还将评估葡萄糖和胰岛素水平的变化， 高、低ANP基因型组之间的挑战。在目标2中，我们将评估EE的差异 （在休息和运动期间）两个基因型组之间。我们还将评估 两个基因型组之间的反应，心钠素，葡萄糖，胰岛素，和标志物的脂肪 挑战标准化的运动。在目标3中，我们将评估miR-425是否发生变化， 低ANP基因型者在糖负荷和运动负荷后的表达。我们亦会评估 miR-425表达变化与MRproANP、葡萄糖和胰岛素水平变化的相关性 在相应的代谢扰动（葡萄糖激发和运动激发）之后。的详细 基于参与者的ANP基因型的代谢谱分析将提供对ANP作用的深入了解。 系统在调节心脏代谢健康，并产生证据支持的生物学基础， 开发基于RNA的新型治疗方法来预防和治疗心脏代谢疾病。

PROJECT SUMMARY The cardiometabolic disease burden is increasing in the United States. The atrial natriuretic peptide (ANP) hormone contributes to the regulation of glucose utilization, energy homeostasis and is a major determinant of cardiometabolic health. We have demonstrated that a common genetic variant in the ANP gene (rs5068) is associated with higher ANP levels and a more favorable cardiometabolic profile. We have also identified that microRNA-425 (miR-425) decreases the production of ANP. The favorable genetic variant (rs5068) prevents the binding of miR-425 and ensures adequate ANP production. Thus, miR-425 acts only among those with low ANP genotype, i.e., those without the rs5068 genetic variant. We have also demonstrated that an oral glucose challenge reduces ANP levels, whereas an exercise challenge increases ANP levels. However, the impact of the ANP genotype on the ANP response to glucose challenge and exercise challenge has not been previously examined. We have demonstrated that miR-425 is glucose-responsive and may regulate the ANP response to metabolic perturbations. The response of miR-425 to glucose challenge, exercise challenge, and its relationship with energy expenditure (EE) is not known in humans. We hypothesize that individuals with low ANP genotype will (1) have a greater suppression of ANP by glucose challenge, (2) have lower resting and exercise EE, and (3) demonstrate the responsiveness of miR-425 to metabolic perturbations (glucose challenge and exercise challenge). We propose to conduct a genotype-guided study by performing detailed metabolic profiling among individuals with high and low ANP genotypes. In our Aim 1, we will enroll 200 healthy adults (50 with high ANP genotype and 150 with low ANP genotype), and we will assess the difference in response of MRproANP to a glucose challenge by genotype groups. We will also assess the change in the glucose and insulin levels subsequent to glucose challenge between high and low ANP genotype groups. In Aim 2, we will assess the difference in EE (during rest and during exercise) between the two genotype groups. We will also assess the difference between the two genotype groups in terms of the response of ANP, glucose, insulin, and markers of fat breakdown to the standardized exercise challenge. In Aim 3, we will assess if there is a change in miR-425 expression after glucose and exercise challenge among those with low ANP genotype. We will also assess the association of change in miR-425 expression with the change in MRproANP, glucose, and insulin levels following respective metabolic perturbations (glucose challenge and exercise challenge). The detailed metabolic profiling of participants based on their ANP genotype will provide insights into the role of the ANP system in the regulation of cardiometabolic health and generate evidence supporting the biological basis for developing RNA-based novel treatment approaches to prevent and treat cardiometabolic diseases.