Biomarkers of Metabolic and Vascular Risk in Obesity

描述（由申请人提供）：与肥胖相关的代谢和血管风险存在相当大的异质性。一些肥胖者有严重的代谢紊乱和血管功能障碍，而另一些肥胖者的代谢状况和血管功能正常。因此，存在不同的“肥胖亚表型”。区分“不健康肥胖”的代谢失调与所谓“健康肥胖”的代谢补偿状态的关键因素包括内脏脂肪增加，特别是脂肪肝，骨骼肌中淀粉样细胞内脂肪量增加，肝脏和骨骼肌胰岛素抵抗，以及有利于血脂异常发展的环境。此外，异位脂肪（脂肪肝和肌肉脂肪）的存在可导致非肥胖人群（“不健康”正常体重）的胰岛素抵抗，这在脂肪营养不良状态中是一个极端的例证。最近的研究强调了脂肪库产生的介质（脂肪因子，ADK）和肝脏在代谢失调的发病机制中的核心作用。这些ADK也可能是肥胖和血管功能障碍之间的关键联系，因为在实验研究中，它们促进不利的血管重塑、内皮功能障碍、动脉粥样硬化斑块形成和交感神经激活。我们假设不健康的肥胖个体会有更高水平的胰岛素抵抗介质、改变的脂肪酸代谢和脂肪肝标志物，即更高的视黄醇结合蛋白-4 （RBP-4）、脂肪细胞-脂肪酸结合蛋白（FABP）和胎儿蛋白a；由于终端器官抵抗，这些人的瘦素水平会很高。相反，健康肥胖者的特点是具有更高水平的适应性介质，如脂联素和抗氧化酶红细胞谷胱甘肽过氧化物酶（GPX1）。因此，我们假设评估关键的肥胖生物标志物（代谢失调和血管功能障碍的基本介质）将区分肥胖亚表型，并前瞻性地预测糖尿病、血脂异常、高血压（HTN）和心血管疾病（CVD）的发病率。我们将通过测量7种循环脂肪生物标志物（瘦素、LEPR、RBP-4、胎儿素- A、FABP-4、脂联素和红细胞GPX1活性）来验证这些假设，这些参与者来自弗雷明汉心脏研究（FHS）第三代（Gen 3）和少数族裔（Omni）队列的4400名中青年参与者（2002-2005）。我们将把这些生物标志物与肥胖亚表型、代谢危险因素和血管功能横断面联系起来（所有这些都是通过其他机制资助的）；纵向跟踪代谢特征。此外，我们将测量与第3代代谢风险和血管功能障碍最密切相关的生物标志物：a.在后代队列（第2代）中，将生物标志物水平与老年人心血管疾病发病率联系起来；b.在第二代第三代检查中，将一系列变化与代谢特征的跟踪联系起来。我们的具体目标是：目标1。肥胖生物标志物和临床/遗传相关性：检查肥胖生物标志物的横截面。我们将进行多变量分析，将肥胖生物标志物（Gen 3和Omni）与代谢危险因素（血压、血糖、胰岛素抵抗和脂质）、肥胖亚表型和腹部脂肪（包括肝脏脂肪）在CT上联系起来。我们将评估遗传力、连锁性，并在选择的候选基因中进行与单核苷酸多态性（snp）相关的生物标志物的关联分析。目标2。肥胖生物标志物和血管重塑：评估肥胖生物标志物（Gen 3和Omni）与微循环功能（外周动脉血压计）的横断面关系；导管动脉、臂动脉内皮功能（超声）和血管硬度（血压计）肥胖生物标志物和结局：将Gen 3和Omni中的肥胖生物标志物（单独和联合）与代谢特征的跟踪以及肥胖、糖尿病、血脂异常和HTN的发生率前瞻性地联系起来；在第2代中，将先前测量的脂联素加1生物标志物（根据第3代Aims 1-2选择）与CVD发病率联系起来；评估一组精简的肥胖生物标志物对现有糖尿病、高血压和心血管疾病发病率风险预测模型的潜在贡献。FHS非常适合这种关注肥胖生物标志物的RFA，因为它提供了：一个大的、单点的、基于社区的中青年男性和女性样本，其中代谢危险因素和血管功能已经得到了很好的表征；现有的CT脂肪测量数据库，神经激素和炎症标志物，通过其他机制资助的密集SNP扫描；持续监测心血管疾病事件；在进行大规模生物标志物研究和风险预测方面有记录的研究。我们认为，目前的申请将通过研究一组肥胖生物标志物及其与社区代谢风险和血管功能障碍的关系，促进我们对肥胖流行病学和相关风险异质性的理解。项目的叙述。肥胖者患心脏病或中风的风险有很大差异：肝脏和腹部脂肪过多的肥胖者更容易患高血压、糖尿病和高胆固醇等风险因素。在这个项目中，弗雷明汉研究的研究人员建议通过血液测试来测量一些“脂肪生物标志物”的水平，这将有助于识别那些更有可能发展成危险因素的肥胖者，从长远来看，他们更容易患心脏病或中风。公共卫生相关性：肥胖者患心脏病或中风的风险存在相当大的差异：肝脏和腹部脂肪过多的肥胖者更容易患高血压、糖尿病和高胆固醇等风险因素。在这个项目中，弗雷明汉研究的研究人员建议通过血液测试来测量一些“脂肪生物标志物”的水平，这将有助于识别那些更有可能发展成危险因素的肥胖者，从长远来看，他们更容易患心脏病或中风。

DESCRIPTION (provided by applicant): There is considerable heterogeneity in the metabolic and vascular risk associated with obesity. Some obese people have profound metabolic derangements and vascular dysfunction, yet others have a normal metabolic profile and vascular function. Thus, there are distinct `obesity subphenotypes.' Key factors that distinguish metabolic dysregulation in `unhealthy obese' from a state of metabolic compensation in so-called `healthy obese' include the presence of increased visceral fat, especially fatty liver, higher amounts of intramyocellular fat in skeletal muscle, hepatic and skeletal muscle insulin resistance, and a milieu conducive to development of dyslipidemia. Further, presence of ectopic fat (fatty liver and muscle fat) can result in insulin resistance in non- obese people (`unhealthy' normal weight), an extreme illustration of which is seen in lipodystrophic states. Recent investigations have highlighted the central role of mediators produced by fat depots (adipokines, ADK) and by the liver in the pathogenesis of metabolic dysregulation. These ADK may also constitute the key link between obesity and vascular dysfunction because they promote adverse vascular remodeling, endothelial dysfunction, atherosclerotic plaque formation, and sympathetic activation in experimental studies. We hypothesize that unhealthy obese individuals will have higher levels of mediators of insulin resistance, altered fatty acid metabolism and markers of a fatty liver, i.e., higher retinol binding protein-4 (RBP-4), adipocyte-fatty acid binding proteins (FABP), and fetuin-A; leptin levels will be high in such people due to end-organ resistance. In contrast, healthy obese people will be characterized by higher levels of adaptive mediators such as adiponectin and the antioxidant enzyme erythrocyte glutathione peroxidase (GPX1). Thus, we postulate that assessment of key adiposity biomarkers, which are fundamental mediators of metabolic dysregulation and vascular dysfunction, will distinguish obesity subphenotypes cross-sectionally, and prospectively predict incidence of diabetes, dyslipidemia, hypertension (HTN) and cardiovascular disease (CVD). We will test these hypotheses by measuring 7 circulating adiposity biomarkers (leptin, LEPR, RBP-4, fetuin- A, FABP-4, adiponectin, and erythrocyte GPX1 activity) in 4400 young-middle aged participants of the third generation (Gen 3) and minority (Omni) cohorts of the Framingham Heart Study (FHS) at their first examination (2002-2005). We will relate these biomarkers cross-sectionally to obesity subphenotypes, metabolic risk factors and vascular function (all funded via other mechanisms); and longitudinally to tracking of metabolic traits. Additionally, we will measure the biomarker most strongly related to metabolic risk and vascular dysfunction in Gen 3: a. in the Offspring cohort (Gen 2) to relate biomarker levels to CVD incidence in older adults; b. at the 2nd Gen 3 exam to relate serial changes to tracking of metabolic traits. Our specific aims are: Aim 1. Adiposity biomarkers, and clinical / genetic correlates: To examine the cross-sectional of adiposity biomarkers. We will perform multivariable analyses to relate adiposity biomarkers (Gen 3 and Omni) to metabolic risk factors (blood pressure, glycemia, insulin resistance, and lipids), obesity subphenotypes, and abdominal fat (including liver fat) on CT. We will assess heritability, linkage, and perform association analyses relating biomarkers to single nucleotide polymorphisms (SNPs) in select candidate genes. Aim 2. Adiposity biomarkers and vascular remodeling: To assess the cross-sectional relations of adiposity biomarkers (Gen 3 and Omni) to: microcirculatory function (peripheral arterial tonometry); and conduit artery brachial artery endothelial function (ultrasound), and vascular stiffness (tonometry) Aim 3. Adiposity biomarkers and outcomes: To prospectively relate adiposity biomarkers (individually and conjointly) in Gen 3 and Omni to the tracking of metabolic traits, and the incidence of obesity, DM, dyslipidemia and HTN; to relate in Gen 2 previously measured adiponectin plus 1 biomarker (chosen based on Gen 3 Aims 1-2) to CVD incidence; to assess the potential contribution of a parsimonious set of adiposity biomarkers to existing risk prediction models for incidence of diabetes, hypertension and CVD. The FHS is well suited for this RFA focusing on biomarkers of obesity because it provides: a large, single-site, community-based sample of young-middle aged men and women in whom metabolic risk factors and vascular function have been well characterized; extant databases of CT fat measures, neurohormonal and inflammatory markers, dense SNP scan funded via other mechanisms; continuous surveillance for CVD events; a study with a track record in conducting large-scale biomarker studies and risk prediction. We submit that the current application will advance our understanding of the epidemiology of obesity and the associated risk heterogeneity by studying a panel of adiposity biomarkers and their relations to metabolic risk, and vascular dysfunction in the community. Project Narrative. There is considerable variation in the risk of suffering a heart attack or stroke among obese individuals: obese people who have excess fat in their liver and around their belly are more likely to develop risk factors such as high blood pressure, diabetes, and high cholesterol levels. In this project, Framingham Study investigators propose to measure levels of some `fatty biomarkers' using blood tests that will help identify those obese people who are more likely to develop risk factors and suffer a heart attack or a stroke in the long run. PUBLIC HEALTH RELEVANCE: There is considerable variation in the risk of suffering a heart attack or stroke among obese individuals: obese people who have excess fat in their liver and around their belly are more likely to develop risk factors such as high blood pressure, diabetes, and high cholesterol levels. In this project, Framingham Study investigators propose to measure levels of some 'fatty biomarkers' using blood tests that will help identify those obese people who are more likely to develop risk factors and suffer a heart attack or a stroke in the long run.