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.

血管加压素通常被视为抗利尿激素，可介导肾脏和尿液浓度的水重吸收，以保护脱水。虽然已知会增加血压，增加血清葡萄糖并堵塞脂肪氧化，但加压素通常不被视为肥胖和代谢综合征的介体。然而，最近的研究表明，在代谢综合征的受试者中，血清copeptin（稳定的加压素生物标志物）升高。此外，我们的初步数据表明，饮食果糖会增加加压素水平，并且果糖诱导的代谢综合征是通过加压素1B（V1B）受体的激活和肝脏中加压素1A（V1A）受体的下调介导的。基于这些观察结果，我们假设加压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。我们提出了三个旨在检验这一假设的目标。 AIM 1将表征其生理和临床相关量的果糖刺激加压素的释放和作用的机制，包括确定果糖暴露后加压素表达的发作，确定它是直接还是卡路里依赖性效应，以及是否是由Liver和liver ins/或ins/in in in in liver and/ne或/或ins/ne ne ructrod介导的。下丘脑。我们还将表征使用下丘脑 - 神经型植物学系统（HNS）Epplants果糖诱导产生，运输，储存和释放的分子机制。 AIM 2将通过两种相反的方法来测试加压素是否在果糖诱导的代谢综合征中起重要作用：通过提供增加的水摄入量（使用水合凝胶）来抑制血清加压素水平，并通过长期抑制用渗透泵将加压素输注。该目标还将确定加压素的有害作用是否是使用V1B - / - 小鼠和V1B特异性拮抗剂对V1B受体的作用介导的。我们还将表征FGF21在V1B介导的果糖诱导的代谢综合征中的作用。 AIM 3将检验以下假设：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双重敲除小鼠的响应，通过下调果糖激酶代谢，通过下调果糖激酶代谢来对抗V1B激活的有害作用至关重要。总而言之，我们的建议的强度是，我们将确定果糖诱导加压素释放，加压素在果糖诱导的代谢综合征中的特定作用以及在此过程中V1A和V1B受体的相反功能。我们的研究将为驱动代谢综合征的机制提供新的见解，尤其是在此过程中水，加压素和果糖的相互作用。