Biomarkers of Metabolic and Vascular Risk in Obesity

Summary

Principal Investigator: Ramachandran S Vasan
Affiliation: Boston University
Country: USA
Abstract: 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.
Funding Period: ----------------2008 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. pmc Circulating ghrelin, leptin, and soluble leptin receptor concentrations and cardiometabolic risk factors in a community-based sample
    Erik Ingelsson
    The Framingham Study, Boston University School of Medicine, Framingham, Massachusetts 01702 5803, USA
    J Clin Endocrinol Metab 93:3149-57. 2008
  2. pmc Cardiometabolic correlates and heritability of fetuin-A, retinol-binding protein 4, and fatty-acid binding protein 4 in the Framingham Heart Study
    Bernhard M Kaess
    National Heart, Blood, and Lung Institute s Framingham Heart Study, Framingham, MA 01702, USA
    J Clin Endocrinol Metab 97:E1943-7. 2012
  3. pmc Relations of circulating resistin and adiponectin and cardiac structure and function: the Framingham Offspring Study
    David D McManus
    National Heart, Lung, and Blood Institute s and Boston University s Framingham Heart Study, Framingham, Massachusetts, USA
    Obesity (Silver Spring) 20:1882-6. 2012
  4. pmc Relation of subcutaneous and visceral adipose tissue to coronary and abdominal aortic calcium (from the Framingham Heart Study)
    Caroline S Fox
    National Heart, Lung and Blood Institute s Framingham Heart Study, Framingham, Massachusetts, USA
    Am J Cardiol 104:543-7. 2009
  5. pmc Association of parental obesity with concentrations of select systemic biomarkers in nonobese offspring: the Framingham Heart Study
    Wolfgang Lieb
    Framingham Heart Study, Framingham, Massachusetts, USA
    Diabetes 58:134-7. 2009
  6. pmc Plasma resistin, adiponectin, and risk of incident atrial fibrillation: the Framingham Offspring Study
    Michiel Rienstra
    Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, USA
    Am Heart J 163:119-124.e1. 2012
  7. pmc Plasma leptin levels and incidence of heart failure, cardiovascular disease, and total mortality in elderly individuals
    Wolfgang Lieb
    Framingham Heart Study, Framingham, Massachusetts, USA
    Diabetes Care 32:612-6. 2009
  8. pmc A multi-marker approach to predict incident CKD and microalbuminuria
    Caroline S Fox
    National Heart, Lung, and Blood Institute s Framingham Heart Study, 73 Mount Wayte Avenue, Suite 2, Framingham, MA 01702, USA
    J Am Soc Nephrol 21:2143-9. 2010
  9. pmc Pericardial fat is associated with prevalent atrial fibrillation: the Framingham Heart Study
    George Thanassoulis
    Framingham Heart Study, Boston University and the National Institutes of Health National Heart, Lung, and Blood Institute, 73 Mt Wayte Ave No 2, Framingham, MA 01702, USA
    Circ Arrhythm Electrophysiol 3:345-50. 2010
  10. pmc Prevalence, distribution, and risk factor correlates of high pericardial and intrathoracic fat depots in the Framingham heart study
    George Thanassoulis
    National Institutes of Health National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, MA, Boston, USA
    Circ Cardiovasc Imaging 3:559-66. 2010

Scientific Experts

  • C S Fox
  • THOMAS J contact WANG
  • Ramachandran S Vasan
  • Wolfgang Lieb
  • Joseph M Massaro
  • Emelia J Benjamin
  • James B Meigs
  • Christopher J O'Donnell
  • Udo Hoffmann
  • Daniel Levy
  • Lisa M Sullivan
  • George Thanassoulis
  • David D McManus
  • Patrick T Ellinor
  • Renate B Schnabel
  • John F Keaney
  • Sander J Robins
  • RALPH B D'AGOSTINO
  • Erik Ingelsson
  • Martin G Larson
  • Tamara B Harris
  • Ronenn Roubenoff
  • Michiel Rienstra
  • Bernhard M Kaess
  • Jayashri Aragam
  • Susan Cheng
  • Sarah R Preis
  • Sarah Rosner Preis
  • Shilpa H Jain
  • Nicole L Glazer
  • Jenny X Sun
  • Christoper J O'Donnell
  • Steven A Lubitz
  • Asya Lyass
  • Vanessa Xanthakis
  • Jared W Magnani
  • Cheryl Ingram
  • Danielle M Enserro
  • David S Frankel
  • Ming Huei Chen
  • Stefan Blankenberg
  • Thomas Illig
  • Abbas Dehghan
  • Patrice Sutherland
  • Christie M Ballantyne
  • Ron C Hoogeveen
  • Jacqueline C M Witteman
  • Norman Klopp
  • Christian Herder
  • Maja Barbalic
  • Eric Boerwinkle
  • Amir A Mahabadi
  • Michelle J Keyes
  • Natalie Khuseyinova
  • Jennifer F Yamamoto
  • Elizabeth L McCabe
  • Nancy S Jenny
  • Jeremy D Walston
  • Paul F Jacques
  • Yanyan Zhu
  • Joshua C Bis
  • Jens Baumert
  • Thomas Irlbeck
  • Sarah L Booth
  • Margaret Doyle
  • Peter Durda
  • Wolfgang Koenig
  • Josee Dupuis
  • Gerardo Heiss
  • Russell P Tracy
  • Cathy Tilley
  • Bruce M Psaty
  • Annette Peters
  • Christian Gieger
  • Alanna C Morrison
  • Myles Wolf
  • Michael J Pencina
  • Sanford Auerbach
  • Katherine J Lanier
  • Annaswamy Raji
  • Guido A Rosito
  • Alexa S Beiser
  • Zaldy S Tan
  • Philip A Wolf
  • Peter W Wilson
  • Geoffrey H Tofler
  • William B Kannel
  • Rhoda Au
  • Sudha Seshadri
  • Charles DeCarli

Detail Information

Publications18

  1. pmc Circulating ghrelin, leptin, and soluble leptin receptor concentrations and cardiometabolic risk factors in a community-based sample
    Erik Ingelsson
    The Framingham Study, Boston University School of Medicine, Framingham, Massachusetts 01702 5803, USA
    J Clin Endocrinol Metab 93:3149-57. 2008
    ..The conjoint effects and relative importance of ghrelin, leptin, and soluble leptin receptor (sOB-R), adipokines involved in appetite control and energy expenditure in mediating cardiometabolic risk, is unknown...
  2. pmc Cardiometabolic correlates and heritability of fetuin-A, retinol-binding protein 4, and fatty-acid binding protein 4 in the Framingham Heart Study
    Bernhard M Kaess
    National Heart, Blood, and Lung Institute s Framingham Heart Study, Framingham, MA 01702, USA
    J Clin Endocrinol Metab 97:E1943-7. 2012
    ..Fetuin-A, retinol-binding protein 4 (RBP4), and fatty-acid binding protein 4 (FABP4) are novel biomarkers that may link adiposity to insulin resistance and the metabolic syndrome (MetSyn)...
  3. pmc Relations of circulating resistin and adiponectin and cardiac structure and function: the Framingham Offspring Study
    David D McManus
    National Heart, Lung, and Blood Institute s and Boston University s Framingham Heart Study, Framingham, Massachusetts, USA
    Obesity (Silver Spring) 20:1882-6. 2012
    ..In conclusion, these associations identify potential mechanisms by which excess adiposity may mediate adverse cardiac remodeling and HF risk...
  4. pmc Relation of subcutaneous and visceral adipose tissue to coronary and abdominal aortic calcium (from the Framingham Heart Study)
    Caroline S Fox
    National Heart, Lung and Blood Institute s Framingham Heart Study, Framingham, Massachusetts, USA
    Am J Cardiol 104:543-7. 2009
    ..However, these cross-sectional associations are attenuated by cardiovascular disease risk factors, possibly because they mediate the association between adiposity measures and subclinical cardiovascular disease...
  5. pmc Association of parental obesity with concentrations of select systemic biomarkers in nonobese offspring: the Framingham Heart Study
    Wolfgang Lieb
    Framingham Heart Study, Framingham, Massachusetts, USA
    Diabetes 58:134-7. 2009
    ..Parental obesity is a risk factor for offspring obesity. It is unclear whether parental obesity also confers risk for obesity-associated conditions (e.g., a proinflammatory or prothrombotic state) in the absence of offspring obesity...
  6. pmc Plasma resistin, adiponectin, and risk of incident atrial fibrillation: the Framingham Offspring Study
    Michiel Rienstra
    Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, USA
    Am Heart J 163:119-124.e1. 2012
    ..Resistin and adiponectin are adipokines that have been associated with multiple known risk factors for AF including diabetes, obesity, inflammation, and heart failure...
  7. pmc Plasma leptin levels and incidence of heart failure, cardiovascular disease, and total mortality in elderly individuals
    Wolfgang Lieb
    Framingham Heart Study, Framingham, Massachusetts, USA
    Diabetes Care 32:612-6. 2009
    ..We tested the hypothesis that leptin levels are associated with greater risk of CHF, CVD, and mortality in elderly individuals...
  8. pmc A multi-marker approach to predict incident CKD and microalbuminuria
    Caroline S Fox
    National Heart, Lung, and Blood Institute s Framingham Heart Study, 73 Mount Wayte Avenue, Suite 2, Framingham, MA 01702, USA
    J Am Soc Nephrol 21:2143-9. 2010
    ..In conclusion, circulating homocysteine, aldosterone, and BNP provide incremental information regarding risk for incident CKD and MA beyond traditional risk factors...
  9. pmc Pericardial fat is associated with prevalent atrial fibrillation: the Framingham Heart Study
    George Thanassoulis
    Framingham Heart Study, Boston University and the National Institutes of Health National Heart, Lung, and Blood Institute, 73 Mt Wayte Ave No 2, Framingham, MA 01702, USA
    Circ Arrhythm Electrophysiol 3:345-50. 2010
    ..We tested the hypothesis that pericardial fat, a unique fat deposit in close anatomic proximity to cardiac structures and autonomic fibers, is associated with prevalent AF...
  10. pmc Prevalence, distribution, and risk factor correlates of high pericardial and intrathoracic fat depots in the Framingham heart study
    George Thanassoulis
    National Institutes of Health National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, MA, Boston, USA
    Circ Cardiovasc Imaging 3:559-66. 2010
    ..We sought to determine the prevalence, distribution, and risk factor correlates of high pericardial and intrathoracic fat deposits...
  11. pmc Neck circumference as a novel measure of cardiometabolic risk: the Framingham Heart study
    Sarah Rosner Preis
    National Heart, Lung, and Blood Institute s and Boston University s Framingham Heart Study, 73 Mount Wayte Avenue, Suite 2, Framingham, Massachusetts 01702, USA
    J Clin Endocrinol Metab 95:3701-10. 2010
    ..Neck circumference, a proxy for upper-body sc fat, may be a unique fat depot that confers additional cardiovascular risk above and beyond central body fat...
  12. pmc Cross-sectional associations between abdominal and thoracic adipose tissue compartments and adiponectin and resistin in the Framingham Heart Study
    Shilpa H Jain
    Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women s Hospital, Boston, Massachusetts, USA
    Diabetes Care 32:903-8. 2009
    ....
  13. pmc Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators
    Renate B Schnabel
    National Heart, Lung, and Blood Institute and Boston University Framingham Heart Study, 73 Mount Wayte Avenue, Framingham, MA 01702 5827, USA
    Blood 115:5289-99. 2010
    ..We have also identified for the first time 2 mechanisms for the release of reservoir chemokines with possible clinical implications...
  14. pmc Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging
    Wolfgang Lieb
    Framingham Heart Study, Framingham, Massachusetts, USA
    JAMA 302:2565-72. 2009
    ..The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes beta-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD)...
  15. pmc Adiposity, cardiometabolic risk, and vitamin D status: the Framingham Heart Study
    Susan Cheng
    Framingham Heart Study, Framingham, Massachusetts, USA
    Diabetes 59:242-8. 2010
    ..Few studies relating vitamin D deficiency to obesity have included direct measures of adiposity. Furthermore, the degree to which vitamin D is associated with metabolic traits after adjusting for adiposity measures is unclear...
  16. pmc Relation of serum leptin with cardiac mass and left atrial dimension in individuals >70 years of age
    Wolfgang Lieb
    Framingham Heart Study, Framingham, Massachusetts, USA
    Am J Cardiol 104:602-5. 2009
    ....
  17. pmc Abdominal subcutaneous and visceral adipose tissue and insulin resistance in the Framingham heart study
    Sarah R Preis
    National Heart, Lung, and Blood Institute s Framingham Heart Study, Framingham, Massachusetts, USA
    Obesity (Silver Spring) 18:2191-8. 2010
    ..003), where VAT had a stronger association in obese individuals. In conclusion, SAT and VAT are both correlates of insulin resistance; however, VAT is a stronger correlate of insulin resistance than SAT...