A Novel Role for Vasopressin in Fructose-Induced Metabolic Syndrome

加压素通常被认为是一种抗利尿激素，它介导肾脏的水重吸收和尿浓度，以防止脱水。虽然已知加压素可以升高血压、升高血糖和阻止脂肪氧化，但加压素通常不被认为是肥胖和代谢综合征的中介。然而，最近的研究表明，代谢综合征患者血清copeptin（一种稳定的抗利尿激素生物标志物）升高。此外，我们的初步数据表明，饮食中的果糖增加了抗利尿激素水平，果糖诱导的代谢综合征是通过肝脏中抗利尿激素1b （V1b）受体的激活和抗利尿激素1a （V1a）受体的下调介导的。基于这些观察，我们假设抗利尿激素在驱动果糖诱导的肥胖和代谢综合征中起着关键的有害作用。我们提出三个目标来检验这一假设。目的1将描述生理和临床相关量的果糖刺激抗利尿激素释放和作用的机制，包括确定果糖暴露后抗利尿激素表达的开始，确定它是直接的还是卡路里依赖的影响，以及它是否由肝脏和/或下丘脑产生抗利尿激素的神经元中的果糖代谢介导。我们还将利用下丘脑-神经垂体系统（HNS）外植体描述果糖诱导抗利尿激素产生、运输、储存和释放的分子机制。目的2将通过两种相反的方法来测试抗利尿激素是否在果糖诱导的代谢综合征中起重要的有害作用：通过增加水摄入量（使用水合凝胶）来抑制血清抗利尿激素水平，以及通过渗透泵长期输注抗利尿激素。该目的还将确定抗利尿激素的有害作用是否通过其对V1b-/-小鼠和V1b特异性拮抗剂的V1b受体的作用介导。我们还将描述FGF21在v1b介导的果糖诱导代谢综合征中的作用。目的3将通过一系列细胞培养和动物研究，包括V1a强制表达和表征V1a/V1b双敲除小鼠的反应，验证肝脏V1a受体在通过下调果糖激酶代谢来对抗V1b激活的有害影响方面发挥重要作用的假设。总之，我们的建议的优势在于，我们将确定果糖诱导抗利尿激素释放的新的和临床相关的机制，抗利尿激素在果糖诱导的代谢综合征中的具体作用，以及在这一过程中V1a和V1b受体的相反功能。我们的研究将为代谢综合征的机制，特别是水、加压素和果糖在这一过程中的相互作用提供新的见解。

Vasopressin is classically considered as the antidiuretic hormone that mediates water reabsorption from the kidney and urinary concentration as a protection from dehydration. While it is known to increase blood pressure, increase serum glucose, and block fat oxidation, vasopressin is usually not considered as a mediator of obesity and metabolic syndrome. However, recent studies demonstrate that serum copeptin (a stable biomarker of vasopressin) is elevated in subjects with metabolic syndrome. Furthermore, our preliminary data indicate that dietary fructose increases vasopressin levels and that fructose-induced metabolic syndrome is mediated by the activation of vasopressin 1b (V1b) receptor and the down-regulation of vasopressin 1a (V1a) receptor in the liver. Based on these observations, we hypothesize that vasopressin plays a key deleterious role in driving fructose-induced obesity and metabolic syndrome. We propose three aims to test this hypothesis. Aim 1 will characterize the mechanisms whereby physiological and clinically relevant amounts of fructose stimulate vasopressin release and action including the determination of the onset of expression of vasopressin following fructose exposure, the determination of whether it is a direct or calorie-dependent effect and if it is mediated by the metabolism of fructose in the liver and/or in vasopressin-producing neurons of the hypothalamus. We will also characterize the molecular mechanisms for fructose induced production, transport, storage and release of vasopressin using hypothalamo-neurohypophyseal system (HNS) explants. Aim 2 will test whether vasopressin plays an important deleterious role in fructose-induced metabolic syndrome by two opposing approaches: by providing increased water intake (using hydrated gel) to suppress serum vasopressin levels, and by chronic infusion of vasopressin with osmotic pumps. This aim will also determine if the deleterious effect of vasopressin is mediated by its action on the V1b receptor using both V1b-/- mice and a V1b specific antagonist. We will also characterize the role of FGF21 in V1b-mediated fructose-induced metabolic syndrome. Aim 3 will test the hypothesis that hepatic V1a receptors are important in counter-regulating the deleterious effects from V1b activation by downregulating fructokinase metabolism, by a series of cell culture and animal studies including V1a forced expression and characterizing the response of V1a/V1b double knockout mice. In summary, the strength of our proposal is that we will identify new and clinically relevant mechanisms whereby fructose induces vasopressin release, the specific role of vasopressin in fructose-induced metabolic syndrome, and the opposite function of the V1a and V1b receptors in this process. Our studies will provide new insights into the mechanisms driving metabolic syndrome, and especially the interaction of water, vasopressin and fructose in this process.