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      Cross‐Sectional Associations of Computed Tomography (CT)‐Derived Adipose Tissue Density and Adipokines: The Framingham Heart Study

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          Abstract

          Background

          Excess accumulation of abdominal subcutaneous ( SAT) and visceral adipose tissue ( VAT) is associated with adverse levels of adipokines and cardiovascular disease risk. Whether fat quality is associated with adipokines has not been firmly established. This study examined the association between abdominal SAT and VAT density, an indirect measure of fat quality, with a panel of metabolic regulatory biomarkers secreted by adipose tissue or the liver independently of absolute fat volumes.

          Methods and Results

          We evaluated 1829 Framingham Heart Study participants (44.9% women). Abdominal SAT and VAT density was estimated indirectly by adipose tissue attenuation using computed tomography. Adipokines included adiponectin, leptin receptor, leptin, fatty acid‐binding protein 4 ( FABP‐4), retinol‐binding protein 4 ( RBP‐4), and fetuin‐A. Fat density was associated with all the biomarkers evaluated, except fetuin‐A. Lower fat density (ie, more‐negative fat attenuation) was associated with lower adiponectin and leptin receptor, but higher leptin and FABP‐4 levels (all P<0.0001). SAT density was inversely associated with RPB‐4 in both sexes, whereas the association between VAT density and RPB‐4 was only observed in men ( P<0.0001). In women, after additional adjustment for respective fat volume, SAT density retained the significant associations with adiponectin, leptin, FABP‐4, and RBP‐4; and VAT density with adiponectin only (all P<0.0001). In men, significant associations were maintained upon additional adjustment for respective fat volume ( P<0.005).

          Conclusions

          Lower abdominal fat density was associated with a profile of biomarkers suggestive of greater cardiometabolic risk. These observations support that fat density may be a valid biomarker of cardiometabolic risk.

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          Most cited references32

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          Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study.

          Visceral adipose tissue (VAT) compartments may confer increased metabolic risk. The incremental utility of measuring both visceral and subcutaneous abdominal adipose tissue (SAT) in association with metabolic risk factors and underlying heritability has not been well described in a population-based setting. Participants (n=3001) were drawn from the Framingham Heart Study (48% women; mean age, 50 years), were free of clinical cardiovascular disease, and underwent multidetector computed tomography assessment of SAT and VAT volumes between 2002 and 2005. Metabolic risk factors were examined in relation to increments of SAT and VAT after multivariable adjustment. Heritability was calculated using variance-components analysis. Among both women and men, SAT and VAT were significantly associated with blood pressure, fasting plasma glucose, triglycerides, and high-density lipoprotein cholesterol and with increased odds of hypertension, impaired fasting glucose, diabetes mellitus, and metabolic syndrome (P range < 0.01). In women, relations between VAT and risk factors were consistently stronger than in men. However, VAT was more strongly correlated with most metabolic risk factors than was SAT. For example, among women and men, both SAT and VAT were associated with increased odds of metabolic syndrome. In women, the odds ratio (OR) of metabolic syndrome per 1-standard deviation increase in VAT (OR, 4.7) was stronger than that for SAT (OR, 3.0; P for difference between SAT and VAT < 0.0001); similar differences were noted for men (OR for VAT, 4.2; OR for SAT, 2.5). Furthermore, VAT but not SAT contributed significantly to risk factor variation after adjustment for body mass index and waist circumference (P < or = 0.01). Among overweight and obese individuals, the prevalence of hypertension, impaired fasting glucose, and metabolic syndrome increased linearly and significantly across increasing VAT quartiles. Heritability values for SAT and VAT were 57% and 36%, respectively. Although both SAT and VAT are correlated with metabolic risk factors, VAT remains more strongly associated with an adverse metabolic risk profile even after accounting for standard anthropometric indexes. Our findings are consistent with the hypothesized role of visceral fat as a unique, pathogenic fat depot. Measurement of VAT may provide a more complete understanding of metabolic risk associated with variation in fat distribution.
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            Visceral fat adipokine secretion is associated with systemic inflammation in obese humans.

            Although excess visceral fat is associated with noninfectious inflammation, it is not clear whether visceral fat is simply associated with or actually causes metabolic disease in humans. To evaluate the hypothesis that visceral fat promotes systemic inflammation by secreting inflammatory adipokines into the portal circulation that drains visceral fat, we determined adipokine arteriovenous concentration differences across visceral fat, by obtaining portal vein and radial artery blood samples, in 25 extremely obese subjects (mean +/- SD BMI 54.7 +/- 12.6 kg/m(2)) during gastric bypass surgery at Barnes-Jewish Hospital in St. Louis, Missouri. Mean plasma interleukin (IL)-6 concentration was approximately 50% greater in the portal vein than in the radial artery in obese subjects (P = 0.007). Portal vein IL-6 concentration correlated directly with systemic C-reactive protein concentrations (r = 0.544, P = 0.005). Mean plasma leptin concentration was approximately 20% lower in the portal vein than in the radial artery in obese subjects (P = 0.0002). Plasma tumor necrosis factor-alpha, resistin, macrophage chemoattractant protein-1, and adiponectin concentrations were similar in the portal vein and radial artery in obese subjects. These data suggest that visceral fat is an important site for IL-6 secretion and provide a potential mechanistic link between visceral fat and systemic inflammation in people with abdominal obesity.
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              The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination.

              For nearly 60 years, the Framingham Heart Study has examined the natural history, risk factors, and prognosis of cardiovascular, lung, and other diseases. Recruitment of the Original Cohort began in 1948. Twenty-three years later, 3,548 children of the Original Cohort, along with 1,576 of their spouses, enrolled in the Offspring Cohort. Beginning in 2002, 4,095 adults having at least one parent in the Offspring Cohort enrolled in the Third Generation Cohort, along with 103 parents of Third Generation Cohort participants who were not previously enrolled in the Offspring Cohort. The objective of new recruitment was to complement phenotypic and genotypic information obtained from prior generations, with priority assigned to larger families. From a pool of 6,553 eligible individuals, 1,912 men and 2,183 women consented and attended the first examination (mean age: 40 (standard deviation: 9) years; range: 19-72 years). The examination included clinical and laboratory assessments of vascular risk factors and imaging for subclinical atherosclerosis, as well as assessment of cardiac structure and function. The comparison of Third Generation Cohort data with measures previously collected from the first two generations will facilitate investigations of genetic and environmental risk factors for subclinical and overt diseases, with a focus on cardiovascular and lung disorders.
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                Author and article information

                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                29 February 2016
                March 2016
                : 5
                : 3 ( doiID: 10.1002/jah3.2016.5.issue-3 )
                : e002545
                Affiliations
                [ 1 ] National Heart, Lung, and Blood Institute's Division of Intramural ResearchThe Framingham Heart Study, and the Population Studies Branch Framingham MA
                [ 2 ] Department of RadiologyMassachusetts General Hospital Boston MA
                [ 3 ] Department of BiostatisticsBoston University Boston MA
                [ 4 ] Division of Cardiovascular MedicineUniversity of Massachusetts Medical School Worcester MA
                [ 5 ] Evans Department of Medicine Whitaker Cardiovascular InstituteBoston University School of Medicine Boston MA
                [ 6 ] Sections of Cardiology and Preventive MedicineBoston University School of Medicine Boston MA
                [ 7 ] Department of EpidemiologyBoston University School of Public Health Boston MA
                [ 8 ] Division of EndocrinologyBrigham and Women's Hospital and Harvard Medical School Boston MA
                Author notes
                [*] [* ] Correspondence to: Caroline S. Fox, MD, MPH, Framingham Heart Study, National Heart, Lung, and Blood Institute, 73 Mount Wayte Ave, Suite 2, Framingham, MA 01702. E‐mail: foxca@ 123456nhlbi.nih.gov
                Article
                JAH31263
                10.1161/JAHA.115.002545
                4943240
                26927600
                ca08c909-84c3-474c-b620-334194be78b9
                © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 10 August 2015
                : 30 November 2015
                Page count
                Pages: 9
                Funding
                Funded by: National Heart, Lung and Blood Institute's Framingham Heart Study
                Award ID: N01‐HC‐25195
                Award ID: R01DK080739
                Categories
                Original Research
                Original Research
                Epidemiology
                Custom metadata
                2.0
                jah31263
                March 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.8.9 mode:remove_FC converted:05.05.2016

                Cardiovascular Medicine
                adipokine,adipose tissue,computed tomography,epidemiology
                Cardiovascular Medicine
                adipokine, adipose tissue, computed tomography, epidemiology

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