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.