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Background: Obesity-related hypertension is a common disorder, and attempts to combat the underlying obesity are often unsuccessful. We previously revealed that mice globally deficient in the inhibitory immunoglobulin G (IgG) receptor FcγRIIB are protected from obesity-induced hypertension. However, how FcγRIIB participates is unknown. Studies were designed to determine if alterations in IgG contribute to the pathogenesis of obesity-induced hypertension., Methods: Involvement of IgG was studied using IgG μ heavy chain-null mice deficient in mature B cells and by IgG transfer. Participation of FcγRIIB was interrogated in mice with global or endothelial cell-specific deletion of the receptor. Obesity was induced by high-fat diet (HFD), and blood pressure (BP) was measured by radiotelemetry or tail cuff. The relative sialylation of the Fc glycan on mouse IgG, which influences IgG activation of Fc receptors, was evaluated by Sambucus nigra lectin blotting. Effects of IgG on endothelial NO synthase were assessed in human aortic endothelial cells. IgG Fc glycan sialylation was interrogated in 3442 human participants by mass spectrometry, and the relationship between sialylation and BP was evaluated. Effects of normalizing IgG sialylation were determined in HFD-fed mice administered the sialic acid precursor N-acetyl-D-mannosamine (ManNAc)., Results: Mice deficient in B cells were protected from obesity-induced hypertension. Compared with IgG from control chow-fed mice, IgG from HFD-fed mice was hyposialylated, and it raised BP when transferred to recipients lacking IgG; the hypertensive response was absent if recipients were FcγRIIB-deficient. Neuraminidase-treated IgG lacking the Fc glycan terminal sialic acid also raised BP. In cultured endothelial cells, via FcγRIIB, IgG from HFD-fed mice and neuraminidase-treated IgG inhibited vascular endothelial growth factor activation of endothelial NO synthase by altering endothelial NO synthase phosphorylation. In humans, obesity was associated with lower IgG sialylation, and systolic BP was inversely related to IgG sialylation. Mice deficient in FcγRIIB in endothelium were protected from obesity-induced hypertension. Furthermore, in HFD-fed mice, ManNAc normalized IgG sialylation and prevented obesity-induced hypertension., Conclusions: Hyposialylated IgG and FcγRIIB in endothelium are critically involved in obesity-induced hypertension in mice, and supportive evidence was obtained in humans. Interventions targeting these mechanisms, such as ManNAc supplementation, may provide novel means to break the link between obesity and hypertension.

Objective: Measures of HDL (high-density lipoprotein) function are associated with cardiovascular disease. However, the effects of regular exercise on these measures is largely unknown. Thus, we examined the effects of different doses of exercise on 3 measures of HDL function in 2 randomized clinical exercise trials., Approach and Results: Radiolabeled and boron dipyrromethene difluoride-labeled cholesterol efflux capacity and HDL-apoA-I (apolipoprotein A-I) exchange were assessed before and after 6 months of exercise training in 2 cohorts: STRRIDE-PD (Studies of Targeted Risk Reduction Interventions through Defined Exercise, in individuals with Pre-Diabetes; n=106) and E-MECHANIC (Examination of Mechanisms of exercise-induced weight compensation; n=90). STRRIDE-PD participants completed 1 of 4 exercise interventions differing in amount and intensity. E-MECHANIC participants were randomized into 1 of 2 exercise groups (8 or 20 kcal/kg per week) or a control group. HDL-C significantly increased in the high-amount/vigorous-intensity group (3±5 mg/dL; P =0.02) of STRRIDE-PD, whereas no changes in HDL-C were observed in E-MECHANIC. In STRRIDE-PD, global radiolabeled efflux capacity significantly increased 6.2% (SEM, 0.06) in the high-amount/vigorous-intensity group compared with all other STRRIDE-PD groups (range, -2.4 to -8.4%; SEM, 0.06). In E-MECHANIC, non-ABCA1 (ATP-binding cassette transporter A1) radiolabeled efflux significantly increased 5.7% (95% CI, 1.2-10.2%) in the 20 kcal/kg per week group compared with the control group, with no change in the 8 kcal/kg per week group (2.6%; 95% CI, -1.4 to 6.7%). This association was attenuated when adjusting for change in HDL-C. Exercise training did not affect BODIPY-labeled cholesterol efflux capacity or HDL-apoA-I exchange in either study., Conclusions: Regular prolonged vigorous exercise improves some but not all measures of HDL function. Future studies are warranted to investigate whether the effects of exercise on cardiovascular disease are mediated in part by improving HDL function., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00962962 and NCT01264406., (© 2018 American Heart Association, Inc.)

Background: Obesity has been linked to the development of hypertension, but whether total adiposity or site-specific fat accumulation underpins this relationship is unclear., Objectives: This study sought to determine the relationship between adipose tissue distribution and incident hypertension., Methods: Normotensive participants enrolled in the Dallas Heart Study were followed for a median of 7 years for the development of hypertension (systolic blood pressure [SBP] ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of blood pressure medications). Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) was quantified by magnetic resonance imaging and proton-spectroscopic imaging, and lower body fat (LBF) was imaged by dual-energy x-ray absorptiometry. Multivariable relative risk regression was performed to test the association between individual fat depots and incident hypertension, adjusting for age, sex, race/ethnicity, diabetes, smoking, SBP, and body mass index (BMI)., Results: Among 903 participants (median age, 40 years; 57% women; 60% nonwhite; median BMI 27.5 kg/m(2)), 230 (25%) developed incident hypertension. In multivariable analyses, higher BMI was significantly associated with incident hypertension (relative risk: 1.24; 95% confidence interval: 1.12 to 1.36, per 1-SD increase). However, when VAT, SAT, and LBF were added to the model, only VAT remained independently associated with incident hypertension (relative risk: 1.22; 95% confidence interval: 1.06 to 1.39, per 1-SD increase)., Conclusions: Increased visceral adiposity, but not total or subcutaneous adiposity, was robustly associated with incident hypertension. Additional studies will be needed to elucidate the mechanisms behind this association., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: Visceral (VAT) and abdominal subcutaneous (SAT) adipose tissues contribute to obesity but may have different metabolic and atherosclerosis risk profiles. We sought to determine the associations of abdominal VAT and SAT mass with markers of cardiac and metabolic risk in a large, multiethnic, population-based cohort of obese adults., Design and Methods: Among obese participants in the Dallas Heart Study, we examined the cross-sectional associations of abdominal VAT and SAT mass, assessed by magnetic resonance imaging (MRI) and indexed to body surface area (BSA), with circulating biomarkers of insulin resistance, dyslipidemia, and inflammation (n = 942); and with aortic plaque and liver fat by MRI and coronary calcium by computed tomography (n = 1200). Associations of VAT/BSA and SAT/BSA were examined after adjustment for age, sex, race, menopause, and body mass index., Results: In multivariable models, VAT significantly associated with the homeostasis model assessment of insulin resistance (HOMA-IR), lower adiponectin, smaller LDL and HDL particle size, larger VLDL size, and increased LDL and VLDL particle number (p < 0.001 for each). VAT also associated with prevalent diabetes, metabolic syndrome, hepatic steatosis, and aortic plaque (p < 0.001 for each). VAT independently associated with C-reactive protein but not with any other inflammatory biomarkers tested. In contrast, SAT associated with leptin and inflammatory biomarkers, but not with dyslipidemia or atherosclerosis. Associations between SAT and HOMA-IR were significant in univariable analyses but attenuated after multivariable adjustment., Conclusion: VAT associated with an adverse metabolic, dyslipidemic, and atherogenic obesity phenotype. In contrast, SAT demonstrated a more benign phenotype, characterized by modest associations with inflammatory biomarkers and leptin, but no independent association with dyslipidemia, insulin resistance, or atherosclerosis in obese individuals. These findings suggest that abdominal fat distribution defines distinct obesity sub-phenotypes with heterogeneous metabolic and atherosclerosis risk., (Copyright © 2012 The Obesity Society.)

Supplemental Digital Content is available in the text. Background: Obesity-related hypertension is a common disorder, and attempts to combat the underlying obesity are often unsuccessful. We previously revealed that mice globally deficient in the inhibitory immunoglobulin G (IgG) receptor FcγRIIB are protected from obesity-induced hypertension. However, how FcγRIIB participates is unknown. Studies were designed to determine if alterations in IgG contribute to the pathogenesis of obesity-induced hypertension. Methods: Involvement of IgG was studied using IgG μ heavy chain–null mice deficient in mature B cells and by IgG transfer. Participation of FcγRIIB was interrogated in mice with global or endothelial cell–specific deletion of the receptor. Obesity was induced by high-fat diet (HFD), and blood pressure (BP) was measured by radiotelemetry or tail cuff. The relative sialylation of the Fc glycan on mouse IgG, which influences IgG activation of Fc receptors, was evaluated by Sambucus nigra lectin blotting. Effects of IgG on endothelial NO synthase were assessed in human aortic endothelial cells. IgG Fc glycan sialylation was interrogated in 3442 human participants by mass spectrometry, and the relationship between sialylation and BP was evaluated. Effects of normalizing IgG sialylation were determined in HFD-fed mice administered the sialic acid precursor N-acetyl-D-mannosamine (ManNAc). Results: Mice deficient in B cells were protected from obesity-induced hypertension. Compared with IgG from control chow–fed mice, IgG from HFD-fed mice was hyposialylated, and it raised BP when transferred to recipients lacking IgG; the hypertensive response was absent if recipients were FcγRIIB-deficient. Neuraminidase-treated IgG lacking the Fc glycan terminal sialic acid also raised BP. In cultured endothelial cells, via FcγRIIB, IgG from HFD-fed mice and neuraminidase-treated IgG inhibited vascular endothelial growth factor activation of endothelial NO synthase by altering endothelial NO synthase phosphorylation. In humans, obesity was associated with lower IgG sialylation, and systolic BP was inversely related to IgG sialylation. Mice deficient in FcγRIIB in endothelium were protected from obesity-induced hypertension. Furthermore, in HFD-fed mice, ManNAc normalized IgG sialylation and prevented obesity-induced hypertension. Conclusions: Hyposialylated IgG and FcγRIIB in endothelium are critically involved in obesity-induced hypertension in mice, and supportive evidence was obtained in humans. Interventions targeting these mechanisms, such as ManNAc supplementation, may provide novel means to break the link between obesity and hypertension. [ABSTRACT FROM AUTHOR]

Obesity and decreased cardiorespiratory fitness (CRF) are independent risk factors for mortality, but higher CRF may minimize the adverse impacts of obesity. Using deep phenotyping, we explored what blood-based and imaging biomarkers were associated with higher CRF among both non-obese and obese individuals in a large multiethnic epidemiological cohort to better understand the biology of the fat but fit phenotype. We performed a cross-sectional analysis of participants enrolled in the Dallas Heart Study between 2007 to 2009 without cardiovascular disease, HIV, cancer, or end-stage renal disease. A total of 2351 individuals were divided into four groups by obesity status (BMI < or ≥30 kg/m2) and CRF (unfit or fit defined as >25th percentile by age and sex, measured using a submaximal treadmill test). Multivariate logistic regression analyses were used to compare circulating biomarkers of cardiometabolic risk, cardiac structure by cardiac magnetic resonance, and adipose depots by dual-energy X-ray absorptiometry between these groups. There were 1052 non-obese and fit, 227 non-obese and unfit, 716 obese and fit, and 356 obese and unfit persons. After adjustment for sex, race, and BMI, factors that were independently associated with fitness in the obese group (versus obese and unfit group) were lower pulse rate (OR, 0.56; 95% CI 0.44-0.71), higher end-diastolic volume indexed to body-surface-area (OR, 1.37; 95% CI 1.06-1.77), and lower subcutaneous fat indexed to body-surface-area (OR, 0.57; 95% CI 0.34-0.96). Lower pulse rate and subcutaneous fat were also associated with being more fit in the non-obese; but contrary to the obese, no cardiac structural measures were statistically significant. These findings suggest that the fat but fit phenotype is characterized by a lower resting pulse, less subcutaneous fat, and a higher left ventricular end-diastolic volume. Being fit is linked to beneficial physiological and cardiovascular changes, irrespective of BMI. [ABSTRACT FROM AUTHOR]

Background: GlycA, an integrated glycosylation protein of five acute phase reactants, is a novel inflammatory biomarker associated with both obesity and cardiovascular disease (CVD). We assessed the hypothesis that visceral adipose tissue (VAT) associates with GlycA and this association may partially explain the pathophysiological link between VAT and CVD. Methods: Baseline measurements of risk factors, body mass index (BMI), waist circumference (WC), and VAT were obtained from 2352 adults in the Dallas Heart Study, a multi-ethnic population-based cohort. GlycA was derived from NMR spectral features. Linear regression was used to assess associations between adiposity variables and GlycA. Cox proportional hazards models were used to assess the associations of VAT and GlycA with first or subsequent CVD event over a median of 11.4 years among those with obesity (BMI >=30). Results: Median age was 43, 56% women and 47% blacks. VAT, BMI and WC were each associated with GlycA in separate models adjusted for traditional risk factors (standardized beta estimates of 0.26, 0.27, and 0.27, respectively; all p < 0.0001). VAT remained directly associated with GlycA when additionally adjusting for BMI or WC. In adjusted models for first and recurrent CV events, the significant direct association between VAT and CV events (HR 1.22, 95% CI 1.04 to 1.44; p=0.01) was partially attenuated when adjusted for GlycA (HR 1.19, 95% CI 1.00 to 1.40; p=0.05). In contrast, VAT remained associated with CV events when adjusted for high sensitivity C-reactive protein. GlycA remained strongly associated with CV events despite adjustment for VAT (HR 1.30, 95% CI 1.13 to 1.49; p=0.0002; Table). Conclusions: Direct imaging assessment of VAT is associated with GlycA, a novel marker of inflammation. The link between VAT and CVD may be partly explained by inflammation reflected by GlycA. These findings suggest that GlycA may be a potentially useful surrogate marker for the adverse CVD risk associated with VAT. [ABSTRACT FROM AUTHOR]