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患者内皮功能的影响

• 批准号: 8711537
• 负责人: Shane A Phillips
• 金额: $ 43.1万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711537
• 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; Complement Factor B; Data; Diet; Dietary Fats; Dietary Intervention; Dissection; Endothelium; Enzymes; Fat-Restricted Diet; Fatty acid glycerol esters; Fluorescent Probes; 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; Prognostic Marker; 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; endothelial dysfunction; feeding; global health; improved; inhibitor/antagonist; lifestyle intervention; mortality; prevent; 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.

描述(由申请人提供)： 肥胖是动脉粥样硬化的危险因素，也是美国发病率和死亡率的主要原因。内皮细胞衍生的一氧化氮(NO)是动脉内稳态的关键调节因子，在动脉粥样硬化的早期阶段就丢失了。肥胖期间NO生物利用度的降低涉及清除NO的活性氧物种(ROS)的生成增加。大多数研究表明，饮食诱导的减肥是体重管理策略的基石，可以改善内皮功能。最近流行的低碳水化合物(LC)饮食对内皮健康的好处是有争议的，因为它们要求以高饮食脂肪含量为代价严格减少碳水化合物的摄入量。例如，我们实验室最近的一项研究显示，等卡路里LC和低脂(LF)饮食对NO介导的内皮依赖性血流介导的扩张(FMD)的影响不同。虽然FMD在LF饮食中得到改善，但在LC饮食中受到损害，这表明LC饮食中体重减轻对NO的潜在好处被否定。这项研究的总体假设是，与等卡路里的低脂肪饮食相比，低碳水化合物饮食通过降低脂联素对内皮活性氧生成的保护作用来减少减肥对内皮功能的好处。因此，LC饮食损害了NO介导的外周阻力动脉内皮依赖性扩张。这一假设得到了初步数据的支持，这些数据表明，LC饮食导致脂联素减少，阻力动脉内皮功能受损。这将在18-40岁的肥胖(BMI：30-39)受试者中进行前瞻性、随机、6周的喂养试验。低脂肪或低碳水化合物饮食将按照卡路里阈值进行管理，以减轻或保持每组的体重。在饮食干预6周之前和之后，皮下脂肪活检获得的分离阻力动脉的内皮依赖性血管扩张功能将被确定。在目标1中，我们将确定与等热量低脂肪饮食相比，在低碳水化合物饮食中，内皮氧化系统对阻力动脉中NO介导的内皮功能降低的贡献。在目标2中，我们将确定低碳水化合物饮食是增加促动脉粥样硬化的脂肪因子，还是减少抗动脉粥样硬化的脂肪因子，或者两者兼而有之。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阻力动脉的内皮功能，以及其机制是否涉及eNOS调节(磷酸化)或超氧化物歧化酶表达。药物抑制剂、ROS和NO的荧光探针、高效液相色谱法和测定酶表达的分子方法将确定ROS和NO在血管组织中产生的位置和来源。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，将提供关于在减肥期间优化大量营养素含量不同的饮食以改善血管功能的机制的临床重要信息。这些结果将开始解决如何使用优化脂联素的生活方式干预措施来预防与高脂肪饮食相关的血管风险。

项目成果

Nox2 contributes to hyperinsulinemia-induced redox imbalance and impaired vascular function.

• DOI: 10.1016/j.redox.2017.06.001
• 发表时间: 2017-10
• 期刊: Redox biology
• 影响因子: 11.4
• 作者: Mahmoud AM;Ali MM;Miranda ER;Mey JT;Blackburn BK;Haus JM;Phillips SA
• 通讯作者: Phillips SA