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

项目总结 在美国，心脏代谢性疾病的负担正在增加。心钠素(ANP) 激素有助于调节葡萄糖的利用，能量平衡，是一个主要的决定因素。 心脏新陈代谢健康。我们已经证明了ANP基因中的一个常见的遗传变异(Rs5068) 与更高的ANP水平和更有利的心脏代谢特征有关。我们还确认了 MicroRNA-425(miR-425)可减少心钠素的产生。有利的遗传变异(Rs5068) 防止miR-425的结合并确保足够的ANP生产。因此，miR-425仅在 低ANP基因携带者，即无rs5068基因变异者。我们还展示了 口服葡萄糖挑战可降低心钠素水平，而运动挑战可提高心钠素水平。 然而，ANP基因型对ANP对葡萄糖挑战和运动的反应的影响 以前没有对挑战进行过审查。我们已经证明miR-425对葡萄糖有反应。 并可能调节心钠素对代谢紊乱的反应。MiR-425对葡萄糖的响应 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)休息和运动EE较低，以及(3)表现出对 MIR-425对代谢扰动(葡萄糖挑战和运动挑战)的影响。我们建议进行一项 在高ANP和低ANP个体中进行详细代谢特征的基因引导研究 基因分型。在我们的目标1中，我们将招募200名健康成年人(50名ANP高基因型，150名低ANP基因型 ANP基因)，我们将通过以下方式评估MRproANP对葡萄糖挑战的反应差异 基因分型组。我们还将评估血糖和胰岛素水平在葡萄糖之后的变化。 高ANP和低ANP基因型组之间的挑战。在目标2中，我们将评估EE的差异 (休息时和运动时)两组之间的差异。我们还将评估差异 在心钠素、血糖、胰岛素和脂肪标志物的反应方面，两个基因型组之间的差异 分解到标准化运动挑战。在目标3中，我们将评估miR-425是否有变化 低ANP基因型者在糖和运动刺激后的表达。我们还将评估 MiR-425表达变化与MRproANP、血糖和胰岛素水平变化的关系 在各自的代谢扰动(葡萄糖挑战和运动挑战)之后。详细的 根据ANP基因型对参与者的代谢情况进行分析将有助于深入了解ANP的作用 调节心脏代谢健康的系统，并产生证据支持 开发基于RNA的预防和治疗心脏代谢性疾病的新治疗方法。

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.