A Novel Role for Vasopressin in Fructose-Induced Metabolic Syndrome

加压素在果糖诱导的代谢综合征中的新作用

基本信息

批准号：
10756244
负责人：
Miguel Angel Lanaspa Garcia
金额：
$ 41.2万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10756244
关键词：
Acceleration Acute Agonist Animals Automobile Driving Biological Markers Calories Cell Culture Techniques Chronic Closure by clamp Data Dehydration Development Diabetes Mellitus Diet Dose Down-Regulation Epidemic FGF21 gene Fatty acid glycerol esters Food Fructokinases Fructose Gel Glucagon Glucose Heat Stress Disorders Hepatic Hormones Human Hydration status Hydrocortisone Hydrogels Hypothalamic structure Infusion procedures Intake Kidney Knockout Mice Liver Measures Mediating Mediator Metabolic Metabolic syndrome Metabolism Molecular Molecular Weight Mus Neurons Obesity Oral Administration Osmolalities Osmolar Concentration Osmosis Pathogenesis Pharmaceutical Preparations Phenotype Physiological Pituitary Gland Play Process Production Publishing Pump Role Series Serum Syndrome System Testing Therapeutic Vasopressin Receptor Vasopressins Visceral fat Water Water consumption Weight Gain Wild Type Mouse absorption antagonist blood pressure elevation clinically relevant dietary epidemiology study experimental study extracellular fibroblast growth factor 21 glucose metabolism high salt diet insight lipid metabolism novel oxidation pharmacologic prevent receptor response soft drink sugar urinary water conservation

项目摘要

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.

加压素通常被认为是一种抗利尿激素，可介导肾脏对水的重吸收和尿液浓缩，从而防止脱水。虽然众所周知，加压素会升高血压、增加血糖并阻止脂肪氧化，但通常不认为它是肥胖和代谢综合征的介质。然而，最近的研究表明，代谢综合征患者的血清和肽素（加压素的稳定生物标志物）升高。此外，我们的初步数据表明，膳食果糖会增加加压素水平，果糖诱导的代谢综合征是通过肝脏中加压素 1b (V1b) 受体的激活和加压素 1a (V1a) 受体的下调介导的。根据这些观察结果，我们假设加压素在驱动果糖引起的肥胖和代谢综合征中发挥着关键的有害作用。我们提出三个目标来检验这一假设。目标 1 将描述生理和临床相关量的果糖刺激加压素释放和作用的机制，包括确定果糖暴露后加压素表达的开始，确定它是直接效应还是卡路里依赖性效应，以及是否是直接效应或卡路里依赖性效应。由肝脏和/或下丘脑产生加压素的神经元中果糖的代谢介导。我们还将利用下丘脑-神经垂体系统（HNS）外植体来表征果糖诱导的加压素产生、运输、储存和释放的分子机制。目标 2 将通过两种相反的方法测试加压素是否在果糖诱导的代谢综合征中发挥重要的有害作用：通过增加水摄入量（使用水合凝胶）来抑制血清加压素水平，以及通过渗透泵长期输注加压素。这一目标还将使用 V1b-/- 小鼠和 V1b 特异性拮抗剂确定加压素的有害作用是否是通过其对 V1b 受体的作用介导的。我们还将描述 FGF21 在 V1b 介导的果糖诱导的代谢综合征中的作用。目标 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 双敲除的反应）来检验以下假设：肝 V1a 受体通过下调果糖激酶代谢，在反调节 V1b 激活的有害影响方面发挥重要作用。老鼠。总之，我们建议的优势在于，我们将确定果糖诱导加压素释放的新的临床相关机制、加压素在果糖诱导的代谢综合征中的具体作用，以及 V1a 和 V1b 受体在此过程中的相反功能。我们的研究将为代谢综合征的驱动机制提供新的见解，特别是在此过程中水、加压素和果糖的相互作用。