Effects of Low Carbohydrate and Low Fat Diets on Endothelium Function in Obesity

低碳水化合物和低脂肪饮食对肥胖症内皮功能的影响

• 批准号: 8319560
• 负责人: Shane A Phillips
• 金额: $ 38.86万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-13 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319560
• 关键词: Acute; Address; Adult; Age; American; Antiatherogenic; Antioxidants; Arteries; Atherosclerosis; Atkins Diet; Attention; Biological Availability; Biopsy; Blood Vessels; Body Weight; Body Weight Changes; Body Weight decreased; Caloric Restriction; Carbohydrates; Cardiovascular Diseases; Cause of Death; Data; Diet; Dietary Fats; Dietary Intervention; Dissection; Endothelium; Enzymes; Fat-Restricted Diet; Fatty acid glycerol esters; Fluorescent Probes; Functional disorder; Generations; Goals; Health; Heart Diseases; High Pressure Liquid Chromatography; Homeostasis; Hypotension; Impairment; Inflammation; Intake; Interleukin-6; Laboratories; Lasers; Leptin; Link; Low-Density Lipoproteins; Macronutrients Nutrition; Masks; Measures; Mediating; Molecular; Morbidity - disease rate; NADPH Oxidase; Nitric Oxide; Nuclear; Obesity; Oxidants; Pathogenesis; Patients; Peripheral Resistance; Phosphorylation; Physiological; Pioglitazone; Production; Randomized; Reactive Oxygen Species; Recommendation; Reducing diet; Regulation; Resistance; Risk; Risk Factors; Signal Transduction; Site; Source; Staging; Superoxide Dismutase; System; TNF gene; Testing; Therapeutic Intervention; Tissues; United States; Vasodilation; Weight; Weight maintenance regimen; Xanthine Oxidase; adipokines; adiponectin; cardiovascular risk factor; catalase; design; disability; feeding; global health; improved; inhibitor/antagonist; lifestyle intervention; mortality; prevent; prognostic indicator; prospective; protective effect; public health relevance; response; subcutaneous; transcription factor; weight maintenance; young man; young woman

DESCRIPTION (provided by applicant): Obesity is a risk factor for atherosclerosis and is a major cause of morbidity and mortality in the United States. Endothelium derived nitric oxide (NO) a key regulator of arterial homeostasis is lost in the early stages of atherosclerosis. Reduced NO bioavailability during obesity involves increased generation of reactive oxygen species (ROS) that scavenge NO. Most studies indicate that diet induced weight loss, the cornerstone of weight management strategies, improves endothelial function. The benefits of the recently popularized low carbohydrate (LC), Atkins' diet, on endothelial health are controversial since they require strict reductions of carbohydrate intake at the expense of high dietary fat content. For instance, a recent study in our laboratory showed divergent effects of isocaloric LC and low fat (LF) diets on NO- mediated endothelium- dependent flow mediated dilation (FMD). While FMD was improved on a LF diet, it was impaired on a LC diet suggesting that the potential benefits of weight loss on NO are negated on LC. The overall hypothesis of this study is that low carbohydrate diets reduce the benefits of weight loss on endothelial function by lowering the protective effect of adiponectin against endothelial reactive oxygen species generation compared to isocaloric low fat diets. Thus, LC diets impair NO- mediated endothelium-dependent dilation of isolated peripheral resistance arteries. This hypothesis is supported by preliminary data indicating adiponectin is reduced and resistance artery endothelial function is impaired on LC diets. This will be tested with a prospective, randomized, 6 week feeding trial in obese (BMI: 30- 39) subjects ages 18-40. Low fat or Low carbohydrate diets will be administered at caloric thresholds designed to either lose or maintain weight in each group. Endothelial- dependent vasodilation will be determined in isolated resistance arteries obtained from subcutaneous fat biopsies before and after 6 weeks of dietary intervention. In aim 1 we will determine the contribution of endothelial oxidant systems on reduced NO- mediated endothelial function in resistance arteries during low carbohydrate diets compared to isocaloric low fat diets. In aim 2 we will determine whether low carbohydrate diets increase pro-atherogenic adipokines, decrease anti-atherogenic adipokines, or both. In aim 3 we will test whether adiponectin improves endothelial function in resistance arteries of subjects on low carbohydrate diets and whether the mechanism involves eNOS regulation (phosphorylation) or superoxide dismutase expression. Pharmacologic inhibitors, fluorescent probes for ROS and NO, HPLC, and molecular approaches of measuring enzyme expression will determine the site and source of ROS and NO production in vascular tissue. Adipokine mediated endothelial dysfunction has been linked to high fat intake and if confirmed on a low carbohydrate diet will provide clinically important information regarding the mechanisms whereby diets differing in macronutrient contents can be optimized to improve vascular function during weight loss. These results will begin to address how lifestyle interventions that optimize adiponectin may be used to prevent the vascular risks associated with diets high in fat. PUBLIC HEALTH RELEVANCE: Obesity is a risk factor for heart disease and a major cause of death and disability in the United States. A variety of weight loss strategies have gained attention including traditional Low Fat (LF) and the recently popularized Low Carbohydrate (LC) diets. The proposed feeding trial will examine the impact of 6 weeks of LF and LC diets designed for body weight loss and maintenance on vascular endothelial function (an early prognostic indicator of the propensity for heart disease) in young men and women.

描述（由申请人提供）： 肥胖是动脉粥样硬化的危险因素，并且是美国发病率和死亡率的主要原因。内皮源性一氧化氮（NO）是动脉稳态的关键调节因子，在动脉粥样硬化的早期阶段丢失。肥胖期间NO生物利用度的降低涉及增加产生的活性氧（ROS），其抑制NO。大多数研究表明，饮食诱导的体重减轻（体重管理策略的基石）改善内皮功能。最近流行的低碳水化合物（LC），阿特金斯饮食，对内皮健康的好处是有争议的，因为他们需要严格减少碳水化合物的摄入量，以牺牲高膳食脂肪含量。例如，我们实验室最近的一项研究表明，等热量LC和低脂（LF）饮食对NO介导的内皮依赖性血流介导扩张（FMD）的影响不同。虽然LF饮食改善了FMD，但LC饮食削弱了FMD，这表明NO减肥的潜在益处在LC上被否定。本研究的总体假设是，与等热量低脂饮食相比，低碳水化合物饮食通过降低脂联素对内皮活性氧产生的保护作用，减少了体重减轻对内皮功能的益处。因此，LC饮食损害NO介导的离体外周阻力动脉的内皮依赖性舒张。这一假设得到了初步数据的支持，表明脂联素减少，阻力动脉内皮功能受损的LC饮食。这将在年龄为18-40岁的肥胖（BMI：30- 39）受试者中进行前瞻性、随机、6周喂养试验。低脂或低碳水化合物饮食将在设计用于减轻或维持每组体重的热量阈值下给药。将在饮食干预6周前后从皮下脂肪活检获得的分离阻力动脉中测定内皮依赖性血管舒张。在目标1中，我们将确定与等热量低脂饮食相比，低碳水化合物饮食期间内皮氧化系统对降低的NO介导的阻力动脉内皮功能的贡献。在目标2中，我们将确定低碳水化合物饮食是否增加促动脉粥样硬化脂肪因子，减少抗动脉粥样硬化脂肪因子，或两者兼而有之。在目标3中，我们将测试脂联素是否改善低碳水化合物饮食受试者的阻力动脉中的内皮功能，以及该机制是否涉及eNOS调节（磷酸化）或超氧化物歧化酶表达。药理学抑制剂、ROS和NO的荧光探针、HPLC和测量酶表达的分子方法将确定血管组织中ROS和NO产生的位点和来源。脂肪因子介导的内皮功能障碍与高脂肪摄入有关，如果在低碳水化合物饮食中得到证实，将提供有关机制的临床重要信息，从而可以优化大量营养素含量不同的饮食，以改善减肥期间的血管功能。这些结果将开始解决如何优化脂联素的生活方式干预可能用于预防与高脂肪饮食相关的血管风险。 公共卫生关系： 肥胖是心脏病的危险因素，也是美国死亡和残疾的主要原因。各种各样的减肥策略得到了关注，包括传统的低脂（LF）和最近流行的低碳水化合物（LC）饮食。拟议的喂养试验将检查6周的LF和LC饮食对年轻男性和女性血管内皮功能（心脏病倾向的早期预后指标）的影响，这些饮食旨在减轻体重和维持体重。