Dietary Salt has an Unrecognized Role in Modulating Energy Intake and Metabolic Syndrome

膳食盐在调节能量摄入和代谢综合征方面的作用尚未被认识

• 批准号: 9114329
• 负责人: Richard Joseph Johnson
• 金额: $ 40.15万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114329
• 关键词: Adipose tissue; Aldehyde Reductase; Animals; Automobile Driving; Blood; Body Weight decreased; Body fat; Brain; Caloric Restriction; Calories; Carbohydrates; Cereals; Clinical; Clinical Trials; Dairy Products; Data; Development; Diabetes Mellitus; Diet; Diet and Nutrition; Eating; Educational process of instructing; Energy Intake; Energy Metabolism; Engineering; Enzymes; Exercise; Expenditure; Fatty Liver; Fatty acid glycerol esters; Food; Food Labeling; Fructokinases; Fructose; Generations; Genes; Genetic Transcription; Glucose; Guidelines; Hepatic; Human; Hyperinsulinism; Hyperphagia; Hypothalamic structure; Individual; Insulin Resistance; Intake; Knockout Mice; L-Iditol 2-Dehydrogenase; Lead; Leptin; Leptin resistance; Link; Literature; Liver; Longitudinal Studies; Mediating; Messenger RNA; Metabolic; Metabolic syndrome; Metabolism; Micronutrients; Mus; Nutritional; Obesity; Organ; Osmolar Concentration; Overweight; Oxidative Stress; Pathogenesis; Pathway interactions; Process; Production; Proteins; Recommendation; Reporting; Research; Resistance; Risk; Role; Signal Transduction; Sodium Chloride; Sorbitol; Source; System; Testing; Up-Regulation; Uric Acid; Water; Weight Gain; bariatric surgery; base; diabetes risk; dietary salt; energy balance; feeding; fructose-1-phosphate; fruits and vegetables; high salt diet; lean body mass; lipid biosynthesis; liver development; novel; nutrition; nutritional guideline; obesity risk; polyol; prevent; public health relevance; reduced food intake; response; salt intake; sugar; transcription factor

 DESCRIPTION (provided by applicant): The classical approach to treat obesity, fatty liver and metabolic syndrome involves dietary calorie restriction, exercise, and, if necessary, bariatric surgery. Most diets focus on reducing energy intake, usually by restricting carbohydrates, proteins, and/or fat. Nutritional guidelines, such as the USDA MyPlate (food pyramid), focus on the caloric content of foods, such as proteins, grains, fruits, vegetables and dairy products. While most diets teach us how to count the calories we eat, rarely is weight loss sustained. It appears like something may be missing. In this proposal, we hypothesize that the non-caloric component of foods has an important, yet unrecognized, role in increasing the risk for obesity, fatty liver and insulin resistance. Based on our preliminary data, we propose that dietary salt, a noncaloric micronutrient present in many foods, has a role in influencing whether carbohydrates will act as simple caloric source or will initiate a metabolic system leading to fatty liver, insuln resistance, decreased leptin sensitivity, and weight gain. We hypothesize that the mechanism whereby dietary salt controls carbohydrate metabolic effects is mediated by its ability to hypertonically up-regulate and activate the aldose reductase-fructokinase system in liver, adipose tissue and brain. Aldose reductase up-regulation is mediated by the activation of the transcription factor associated to hypertonicity TonEBP/NFAT5 that stimulates the transcription of aldose reductase among other osmo-regulated genes. Activation of aldose reductase in these organs results in the generation of endogenous sorbitol and fructose from glucose. Metabolism of this endogenous fructose through fructokinase drives fat production and insulin resistance in the liver while inducing leptin release in adipose tissue and central decreased leptin sensitivity n the hypothalamus. Aim 1 will test the hypothesis that salty foods raise hepatic and blood tonicity, thereby activating TonEBP, aldose reductase and the fructokinase pathway. This activation leads to endogenous fructose production, fat accumulation and insulin resistance. Also, we will study if this process occurs in animals when salt intake is provided under isoosmolar conditions. Aim 2 will test the hypothesis that salt-induced metabolic syndrome (especially insulin resistance and fatty liver) can occur in isocaloric conditions. Also, we will tst if reduced central leptin sensitivity is an important step in the pathogenesis of salt-induced metabolic syndrome These studies may modify current views on the role of nutrition in obesity and metabolic syndrome, by revealing the importance of the non-caloric component of foods. While simple in concept, our studies could modify current scientific paradigms for nutrition and diet that could lead to changes in food labeling, nutrition and the dietary management of individuals who are overweight or obese.

 描述（由申请人提供）：治疗肥胖、脂肪肝和代谢综合征的经典方法包括饮食热量限制、锻炼以及必要时的减肥手术。大多数饮食侧重于减少能量摄入，通常通过限制碳水化合物、蛋白质和/或脂肪来实现。营养指南，例如美国农业部 MyPlate（食物金字塔），重点关注食物的热量含量，例如蛋白质、谷物、水果、蔬菜和乳制品。虽然大多数节食方法都教我们如何计算摄入的卡路里，但很少能持续减肥。看起来好像可能缺少一些东西。在这项提议中，我们假设食物中的非热量成分在增加肥胖、脂肪肝和胰岛素抵抗的风险方面具有重要但未被认识到的作用。根据我们的初步数据，我们提出膳食盐（一种存在于许多食物中的无热量微量营养素）在影响碳水化合物是否作为简单的热量来源或启动导致脂肪肝、胰岛素抵抗、瘦素敏感性降低和体重增加的代谢系统方面发挥作用。我们假设膳食盐控制碳水化合物代谢作用的机制是通过其高渗上调和激活肝脏、脂肪组织和大脑中醛糖还原酶-果糖激酶系统的能力介导的。醛糖还原酶上调是通过与高渗性 TonEBP/NFAT5 相关的转录因子的激活介导的，TonEBP/NFAT5 刺激其他渗透调节基因中醛糖还原酶的转录。这些器官中醛糖还原酶的激活导致葡萄糖产生内源山梨醇和果糖。这种内源性果糖通过果糖激酶的代谢驱动肝脏中的脂肪产生和胰岛素抵抗，同时诱导脂肪组织中的瘦素释放和下丘脑中枢的瘦素敏感性降低。目标 1 将检验咸味食物会提高肝脏和血液张力，从而激活 TonEBP、醛糖还原酶和果糖激酶途径的假设。这种激活导致内源性果糖产生、脂肪积累和胰岛素抵抗。此外，我们还将研究在等渗条件下摄入盐时，动物身上是否会发生这一过程。目标 2 将检验盐诱导的代谢综合征（尤其是胰岛素抵抗和脂肪肝）可能在等热量条件下发生的假设。此外，我们还将测试中枢瘦素敏感性降低是否是盐诱导代谢综合征发病机制的重要一步。这些研究可能通过揭示食物非热量成分的重要性，改变目前关于营养在肥胖和代谢综合征中的作用的观点。虽然概念简单，但我们的研究可以修改当前营养和饮食的科学范式，从而可能导致食品标签、营养和超重或肥胖个体的饮食管理发生变化。