HIV infection and antiretroviral therapy are associated with dyslipidemia, but the association between regional body fat and lipid levels is not well described.
Multivariable linear regression analyzed the association between magnetic resonance imaging–measured regional adipose tissue and fasting lipids in 284 HIV-infected and 129 control women.
Among African Americans, HIV-infected women had higher triglyceride (116 vs. 83 mg/dL; P < 0.001), similar high-density lipoprotein (HDL; 52 vs. 50 mg/dL; P = 0.60), and lower low-density lipoprotein (LDL; 99 vs. 118 mg/dL; P = 0.008) levels than controls. Among whites, HIV-infected women had higher triglyceride (141 vs. 78 mg/dL; P < 0.001), lower HDL (46 vs. 57 mg/dL; P < 0.001), and slightly lower LDL (100 vs. 107 mg/dL; P = 0.059) levels than controls. After adjustment for demographic and lifestyle factors, the highest tertile of visceral adipose tissue (VAT) was associated with higher triglyceride (+85%, 95% confidence interval [CI]: 55 to 121) and lower HDL (−9%, 95% CI: −18 to 0) levels in HIV-infected women; the highest tertile of leg subcutaneous adipose tissue (SAT) was associated with lower triglyceride levels in HIV-infected women (−28%, 95% CI: −41 to −11) and controls (−39%, 95% CI: −5 to −18). After further adjustment for adipose tissue, HIV infection remained associated with higher triglyceride (+40%, 95% CI: 21 to 63) and lower LDL (−17%, 95% CI: −26 to −8) levels, whereas HIV infection remained associated with lower HDL levels (−21%, 95% CI: −29 to −12) in whites but not in African Americans (+8%, 95% CI: −2 to 19).
HIV-infected white women are more likely to have proatherogenic lipid profiles than HIV-infected African American women. Less leg SAT and more VAT are important factors associated with adverse lipid levels. HIV-infected women may be at particular risk for dyslipidemia because of the risk for HIV-associated lipoatrophy.
dyslipidemia; fat distribution; HIV infection; lipid levels; lipodystrophy; women
Coinfection with hepatitis C virus (HCV) is reported to be associated with a higher prevalence of lipodystrophy than HIV infection alone. We examine the association between HCV and adipose tissue volume in HIV-infected men and women.
Cross-sectional analysis of HIV-infected subjects from the study of Fat Redistribution and Metabolic Change in HIV Infection. MRI measured regional adipose tissue volume. Detectable HCV RNA defined HCV infection.
Twenty percent of 792 men and 26% of 329 women were HIV/HCV-coinfected. HIV/HCV-coinfected and HIV-monoinfected women had similar amounts of subcutaneous adipose tissue (SAT) in the leg, lower trunk, upper trunk, and arm and similar amounts of visceral adipose tissue (VAT). Similar findings were seen in men, except in the leg and VAT. After adjustment, HCV infection remained associated with more leg fat in men (12.2%, 95% confidence interval [CI]: 0.3 to 25.3; P = 0.043). Among those on stavudine, HIV-monoinfected men had less leg fat (−7% effect per year of stavudine use, 95% CI: −9 to −5; P < 0.001); a weaker association was seen in HIV/HCV-coinfected men (−2% effect, 95% CI: −7 to 3; P = 0.45). Indinavir was associated with less leg fat (−4% in HIV-monoinfected men, 95% CI: −6 to −1; P = 0.002; −5% in HIV/HCV-coinfected men, 95% CI: −11 to 2; P = 0.14).
Our findings suggest that HIV/HCV coinfection is not associated with less SAT in men and women. HCV infection seems to mitigate the loss of leg fat seen in HIV-infected men on stavudine.
adipose tissue volume; fat distribution; hepatitis C virus; HIV; lipodystrophy
Visceral obesity is associated with insulin resistance, but the association of other regional adipose depots with insulin resistance is not understood. In HIV infection, buffalo hump (upper trunk fat) is associated, but the association of upper trunk fat with insulin resistance has not been examined in controls. To determine the independent association of adipose depots other than visceral with insulin resistance, we performed a cross-sectional analysis of controls and HIV-infected subjects in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study, who had measurements of glucose, insulin, and adipose tissue volumes by whole-body magnetic resonance imaging. We studied 926 HIV-positive persons from 16 academic medical center clinics and trials units with demographic characteristics representative of US patients with HIV infection and 258 FRAM controls from the population-based Coronary Artery Risk Development in Young Adults study. We measured visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume in the legs, arms, lower trunk (back and abdomen), and upper trunk (back and chest) and assessed their association with the homeostasis model of assessment (HOMA) and HOMA >4 by stepwise multivariable analysis. The prevalence of HOMA >4 as a marker of insulin resistance was 28% among controls compared with 37% among HIV-infected subjects (P = 0.005). Among controls, those in the highest tertile of upper trunk SAT volume had an odds ratio (OR) of 9.0 (95% confidence interval [CI]: 2.4 to 34; P = 0.001) for having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was lower (OR = 2.09, 95% CI: 1.36 to 3.19; P = 0.001). Among controls, the highest tertile of VAT volume had an OR of 12.1 (95% CI: 3.2 to 46; P = 0.0002) of having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was 3.12 (95% CI: 2.0 to 4.8; P < 0.0001). After adjusting for VAT and upper trunk SAT, the association of other SAT depots with HOMA >4 did not reach statistical significance. Thus, VAT and upper trunk SAT are independently associated with insulin resistance in controls and in HIV-infected persons.
buffalo hump; fat distribution; insulin resistance; lipodystrophy; visceral obesity
A large proportion of HIV-infected subjects on antiretroviral medication develop insulin resistance, especially in the context of fat redistribution. This study investigates the interrelationships among fat distribution, hepatic lipid content, and insulin resistance in HIV-infected men.
Design and methods
We performed a cross-sectional analysis of baseline data from twenty-three HIV-infected participants in 3 prospective clinical studies. Magnetic resonance spectroscopy was applied to quantify hepatic lipid concentrations. Magnetic resonance imaging was used to quantify whole body adipose tissue compartments, i.e., subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes as well as inter-muscular adipose tissue (IMAT) subcompartment, and omental-mesenteric adipose tissue (OMAT) and retroperitoneal adipose tissue (RPAT) subcompartments of VAT. Homeostasis model for assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations.
Hepatic lipid content correlated significantly with total VAT (r=0.62, p=0.0014) but not with SAT (r=0.053, p=0.81). In univariate analysis, hepatic lipid content was associated with the OMAT (r=0.67, p=0.0004) and RPAT (r=0.53, p=0.009) subcompartments; HOMA-IR correlated with both VAT and hepatic lipid contents (r=0.61, p=0.057 and 0.68, p=0.0012, respectively). In stepwise linear regression models, hepatic lipid had the strongest associations with OMAT and with HOMA-IR.
Hepatic lipid content is associated with VAT volume, especially the omental-mesenteric subcompartment, in HIV-infected men. Hepatic lipid content is associated with insulin resistance in HIV-infected men. Hepatic lipid content might mediate the relationship between VAT and insulin resistance among treated, HIV-infected men.
liver fat; visceral adipose tissue; subcutaneous adipose tissue; inter-muscular adipose tissue; omental-mesenteric adipose tissue; retroperitoneal adipose tissue; HOMA; insulin resistance; HIV
Genetic studies may help explain abnormalities of fat distribution in HIV-infected patients treated with antiretroviral therapy (ARV).
Subcutaneous adipose tissue (SAT) volume measured by magnetic resonance imaging (MRI) in leg, lower trunk, upper trunk, and arm was examined in 192 HIV-infected Caucasian men, ARV-treated from the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study. Single nucleotide polymorphisms (SNPs) were assayed using the Illumina HumanCNV370-quad beadchip. Multivariate and univariate genome wide association analyses of the four SAT depots were implemented in PLINK software adjusted for age and ARV duration. Functional annotation analysis (FAA) using Ingenuity Systems Pathway Analysis tool (IPA) was carried out for markers with P<10-3 near known genes identified by multivariate analysis.
Loci (rs10504906, rs13267998, rs921231) in or near the anion exchanger solute carrier family 26, member 7 isoform a (SLC26A7) were strongly associated with upper trunk and arm SAT (9.8*10-7≤P<7.8*10-6). Loci (rs193139, rs7523050, rs1761621) in and near a gene rich region including G-protein-signaling modulator 2 (GPSM2) and syntaxin binding protein 3 (STXBP3) were significantly associated with lower body SAT depots (9.9*10-7≤P<9.5*10-6). GPSM2 is associated with cell division and cancer while STXBP3 is associated with glucose metabolism in adipoctyes. IPA identified atherosclerosis, mitochondrial function and T-Cell mediated apoptosis as processes related to SAT volume in HIV-infected individuals (P<5*10-3).
Our results are limited by the small sample size and replication is needed, however this genomic scan uncovered new genes associated with metabolism and inflammatory pathways that may affect SAT volume in ARV-treated HIV-infected patients.
HIV; HAART; GWAS; Subcutaneous Fat; SAT
Loss of subcutaneous (SAT) with sparing of visceral (VAT) adipose tissue (AT) has been documented in HIV + men and women. Intermuscular AT (IMAT) rivals VAT in independent associations with cardiovascular risk.
To determine whether the size and distribution of IMAT differs in HIV+ vs. HIV- men and/or women.
We used whole-body MRI to measure VAT, IMAT and four SAT compartments and compared them by HIV status using whole-body skeletal muscle (SM) or total AT (TAT) as co-variates in multi-ethnic groups of healthy HIV- (n=86) and stable HIV+ (n=76) men and women.
The sizes of AT depots (adjusting for SM) did not differ by HIV status, except for smaller gluteal SAT (lower trunk, between L4-L5 to greater trochanter) in both sexes (P<0.05). The AT distribution (adjusting for TAT) was significantly different, with larger VAT (P<0.05) and smaller gluteal and limb SAT (P<0.05) in both HIV+ sexes; IMAT increased more with TAT in HIV+ vs. HIV- men (P<0.05 for slope interaction) but there were no significant differences in women. There were significant race by HIV interactions in AT distribution with more pronounced VAT differences in non-Hispanic white men and larger trunk SAT in African Americans HIV+ vs. HIV-.
The AT distribution differed markedly in HIV+ vs. HIV- with limb and lower body SAT representing a smaller proportion of TAT in HIV+ in both sexes and IMAT representing a larger proportion of TAT in HIV+ vs. HIV- men.
fat distribution; muscle adipose tissue infiltration; HIV; magnetic resonance imaging
Altered fat distribution is associated with insulin resistance in HIV, but little is known about regional glucose metabolism in fat and muscle depots in this patient population. The aim of the present study was to quantify regional fat, muscle, and whole body glucose disposal in HIV-infected men with lipoatrophy. Whole body glucose disposal was determined by hyperinsulinemic clamp technique (80 mU·m−2·min−1) in 6 HIV-infected men and 5 age/weight-matched healthy volunteers. Regional glucose uptake in muscle and subcutaneous (SAT) and visceral adipose tissue (VAT) was quantified in fasting and insulin-stimulated states using 2-deoxy-[18F]fluoro-d-glucose positron emission tomography. HIV-infected subjects with lipoatrophy had significantly increased glucose uptake into SAT (3.8 ± 0.4 vs. 2.3 ± 0.5 μmol·kg tissue−1·min−1, P < 0.05) in the fasted state. Glucose uptake into VAT did not differ between groups. VAT area was inversely related with whole body glucose disposal, insulin sensitivity, and muscle glucose uptake during insulin stimulation. VAT area was highly predictive of whole body glucose disposal (r2 = 0.94, P < 0.0001). This may be mediated by adiponectin, which was significantly associated with VAT area (r =−0.75, P = 0.008), and whole body glucose disposal (r = 0.80, P = 0.003). This is the first study to directly demonstrate increased glucose uptake in subcutaneous fat of lipoatrophic patients, which may partially compensate for loss of SAT. Furthermore, we demonstrate a clear relationship between VAT and glucose metabolism in multiple fat and muscle depots, suggesting the critical importance of this depot in the regulation of glucose and highlighting the significant potential role of adiponectin in this process.
positron emission tomography; adipose tissue; insulin resistance; human immunodeficiency virus-lipodystrophy
HIV-infected individuals are at increased risk for cardiovascular disease (CVD) and lipodystrophy, but the relationship between regional adipose tissue (AT) depots and CVD risk is not well-described. We determined regional AT volumes and CVD risk in an analysis of 586 HIV-infected and 280 control FRAM study subjects using whole-body magnetic resonance imaging (MRI) and the Framingham Risk Score (FRS). Median FRS and FRS >10% were higher in HIV than control men (4.7% vs. 3.7%, p=0.0002; 16% vs. 4%, p<0.0001). HIV and control women had similarly-low FRS (1.1% vs. 1.2%, p=0.91). In controls, total AT and all regional AT depots showed strong positive correlations with FRS (p<0.001) in men, and weaker positive correlations in women. Greater visceral AT (VAT) and lower leg subcutaneous AT (SAT) volumes were associated with elevated FRS in HIV subjects, with a trend for upper trunk SAT. Controls in the lowest quartile of leg SAT had the lowest FRS (1.5%), whereas HIV with similarly-low leg SAT had the highest FRS (4.0%, p<0.001 vs. controls). Increased VAT is associated with CVD risk, but the risk is higher in HIV-infected individuals relative to controls at every level of VAT. Peripheral lipoatrophy (as measured by leg SAT) is associated with striking increased CVD risk in HIV-infected patients, even after controlling for VAT, whereas low leg SAT is associated with low CVD risk in controls.
HIV; fat redistribution; lipoatrophy; visceral fat; cardiovascular risk
Both peripheral fat loss and central fat gain have been reported in women with HIV infection. We determined the fat changes that are specific to HIV infection in women.
HIV-infected and control women from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) were compared. Lipoatrophy or lipohypertrophy was defined as concordance between participant report of fat change and clinical examination. Whole-body magnetic resonance imaging measured regional adipose tissue volumes. The relationship among different adipose tissue depots was assessed. Factors associated with individual depots were analyzed using multivariate linear regression.
HIV-infected women reported more fat loss than controls in all peripheral and most central depots. Peripheral lipoatrophy was more frequent in HIV-infected women than controls (28% vs. 4%, P < 0.001), whereas central lipohypertrophy was similar (62% vs. 63%). Among HIV-infected women, those with central lipohypertrophy were less likely to have peripheral lipoatrophy (odds ratio, 0.39; 95% confidence interval, 0.20 to 0.75, P = 0.006) than those without central lipohypertrophy. On magnetic resonance imaging, HIV-infected women with clinical peripheral lipoatrophy had less subcutaneous adipose tissue (SAT) in peripheral and central sites and less visceral adipose tissue (VAT) than HIV-infected women without peripheral lipoatrophy. Compared with controls, HIV-infected women had less SAT in the legs, regardless of the presence or absence of lipoatrophy. However, those without lipoatrophy had more VAT and upper trunk SAT than controls. Use of the antiretroviral drug stavudine was associated with less leg SAT but was not associated with VAT. The use of highly active antiretroviral therapy, however, was associated with more VAT.
Peripheral lipoatrophy occurs commonly in HIV-infected women but is not associated with reciprocally increased VAT or trunk fat.
HIV; lipodystrophy; lipoatrophy; lipohypertrophy; visceral obesity; fat redistribution; body composition
Both peripheral fat loss and central fat gain have been reported in HIV infection. Which changes are specific to HIV were determined by comparison with control subjects and the associations among different adipose tissue depots were determined.
Cross-sectional analysis of HIV-positive and control men from the study of Fat Redistribution and Metabolic Change in HIV Infection. Lipoatrophy or lipohypertrophy was defined as concordance between participant report of change and examination. Regional adipose tissue volume was measured by magnetic resonance imaging (MRI).
HIV-positive men reported more fat loss than controls in all peripheral and most central depots. Peripheral lipoatrophy was more frequent in HIV-positive men than in controls (38.3% vs. 4.6%, P < 0.001), whereas central lipohypertrophy was less frequent (40.2% vs. 55.9%, P = 0.001). Among HIV-positive men, the presence of central lipohypertrophy was not positively associated with peripheral lipoatrophy (odds ratio = 0.71, CI: 0.47 to 1.06, P = 0.10). On MRI, HIV-positive men with clinical peripheral lipoatrophy had less subcutaneous adipose tissue (SAT) in peripheral and central sites and less visceral adipose tissue (VAT) than HIV-positive men without peripheral lipoatrophy. HIV-positive men both with and without lipoatrophy had less SAT than controls, with legs and lower trunk more affected than upper trunk. Use of the antiretroviral drugs stavudine or indinavir was associated with less leg SAT but did not appear to be associated with more VAT; nevirapine use was associated with less VAT.
Both peripheral and central subcutaneous lipoatrophy was found in HIV infection. Lipoatrophy in HIV-positive men is not associated with reciprocally increased VAT.
HIV infection; lipodystrophy; lipoatrophy; lipohypertrophy; visceral obesity; fat redistribution; body composition
OBJECTIVE—Insulin resistance and type 2 diabetes are associated with an atherogenic lipoprotein profile. We examined the role of visceral and subcutaneous fat depots, independent of BMI, on the dyslipidemia associated with type 2 diabetes.
RESEARCH DESIGN AND METHODS— A total of 382 subjects with type 2 diabetes underwent abdominal computed tomography to evaluate subcutaneous (SAT) and visceral adipose tissue (VAT) distribution and had anthropometric measurements to determine BMI and waist and hip circumference. Fasting blood was obtained for lipoprotein particle number and size using nuclear magnetic resonance spectroscopy. The relationship of lipoprotein particle number and size with BMI, SAT, and VAT was examined using multivariable regression models adjusted for age, sex, diabetes therapy, duration of diabetes, smoking, statin use, and A1C levels. The relation of VAT to lipoprotein particle number and size was further evaluated after the addition of BMI, BMI plus SAT, or BMI plus homeostatis is model assessment of insulin resistance (HOMA-IR) to the model.
RESULTS—VAT was positively related to VLDL particle number (P < 0.0001), LDL particle number (P < 0.01), and VLDL size (P < 0.0001) and negatively related to LDL size (P < 0.0001) and HDL size (P < 0.0001). These relationships remained unchanged after addition of BMI and SAT to the model. After addition of HOMA-IR, VAT remained positively related to VLDL particle number (P < 0.0001) and size (P < 0.01) and negatively related to LDL and HDL particle size (P < 0.0001 for both comparisons). Neither BMI nor SAT was independently related to lipoprotein parameters.
CONCLUSIONS—In patients with type 2 diabetes, higher VAT independent of BMI was associated with higher VLDL and LDL particle number, larger VLDL particles, and smaller LDL and HDL particles. This lipoprotein pattern has been associated with increased risk for atherosclerosis and cardiovascular disease.
To test the association of regional fat depots with circulating adiponectin and resistin concentrations and to assess the potential mediating effect of adipokines on associations between abdominal fat depots and cardiometabolic risk factors.
RESEARCH DESIGN AND METHODS
Participants from the Framingham Heart Study offspring cohort (n = 916, 55% women; mean age 59 years) free of cardiovascular disease underwent computed tomography measurement of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), pericardial fat, and intrathoracic fat volumes and assays of circulating adiponectin and resistin.
VAT, SAT, pericardial fat, and intrathoracic fat were negatively correlated with adiponectin (r = −0.19 to −0.34, P < 0.001 [women]; r = −0.15 to −0.26, P < 0.01 [men] except SAT) and positively correlated with resistin (r = 0.16–0.21, P < 0.001 [women]; r = 0.11–0.14, P < 0.05 [men] except VAT). VAT increased the multivariable model R2 for adiponectin from 2–4% to 10–13% and for resistin from 3–4% to 3–6%. Adjustment for adipokines did not fully attenuate associations between VAT, SAT, and cardiometabolic risk factors.
Adiponectin and resistin are correlated with fat depots cross-sectionally, but none of the adipokines can serve as surrogates for the fat depots. Relations between VAT, SAT, and cardiometabolic risk factors were not fully explained by adiponectin or resistin concentrations.
Although half of HIV-infected patients develop lipodystrophy and metabolic complications, there exists no simple clinical screening tool to discern the high from the low-risk HIV-infected patient. Thus, we evaluated the associations between waist circumference (WC) combined with triglyceride (TG) levels and the severity of lipodystrophy and cardiovascular risk among HIV-infected men and women.
1481 HIV-infected men and 841 HIV-infected women were recruited between 2005 and 2009 at the metabolic clinic of the University of Modena and Reggio Emilia in Italy. Within each gender, patients were categorized into 4 groups according to WC and TG levels. Total and regional fat and fat-free mass were assessed by duel-energy x-ray absorptiometry, and visceral adipose tissue (VAT) and abdominal subcutaneous AT (SAT) were quantified by computed tomography. Various cardiovascular risk factors were assessed in clinic after an overnight fast.
The high TG/high WC men had the most VAT (208.0±94.4 cm2), as well as the highest prevalence of metabolic syndrome (42.2%) and type-2 diabetes (16.2%), and the highest Framingham risk score (10.3±6.5) in comparison to other groups (p<0.05 for all). High TG/high WC women also had elevated VAT (150.0±97.9 cm2) and a higher prevalence of metabolic syndrome (53.3%), hypertension (30.5%) and type-2 diabetes (12.0%), and Framingham risk score(2.9±2.8) by comparison to low TG/low WC women (p<0.05 for all).
A simple tool combining WC and TG levels can discriminate high- from low-risk HIV-infected patients.
OBJECTIVE— The purpose of this study was to assess the relationship between lifestyle factors and abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in a community-based setting.
RESEARCH DESIGN AND METHODS— Cross-sectional associations between lifestyle factors (dietary quality, physical activity, smoking, and alcohol consumption) and SAT and VAT volumes were examined in 2,926 Framingham Heart Study participants (48.6% women, aged 50 ± 10 years).
RESULTS— Diets consistent with the 2005 Dietary Guidelines Adherence Index and greater physical activity were inversely associated with SAT and VAT (P < 0.0001–0.002). In men, former smoking was associated with higher SAT (2,743 ± 56 cm3) compared with current smokers (2,629 ± 88 cm3) or those who never smoked (2,538 ± 44 cm3; P = 0.02). Both former and current smoking was associated with higher VAT (P = 0.03 [women]; P = 0.005 [men]). Women with high amounts of alcohol intake (>7 drinks/week) had lower SAT (2,869 ± 106 cm3) than those who consumed less alcohol (3,184 ± 44 cm3, P = 0.006); significant differences in VAT were not observed (P = 0.18). In men, high amounts of alcohol intake (>14 drinks/week) were associated with higher VAT (2,272 ± 59 cm3) compared with intake of ≤14 drinks/week (2,139 ± 25 cm3, P = 0.04), whereas SAT did not differ (P = 0.91). An increasing number of healthy lifestyle factors were associated with lower SAT and VAT volumes (all P < 0.003).
CONCLUSIONS— Adherence to recommended dietary guidelines and physical activity are associated with lower SAT and VAT volumes. However, both smoking and high alcohol intake are differentially associated with VAT volumes. Further research to uncover the putative mechanisms is warranted.
Inflammation is a potential mechanism to explain the accelerated atherosclerosis observed in HIV- and hepatitis C virus (HCV)–infected persons. We evaluated C-reactive protein (CRP) in HIV-infected and HIV/HCV-coinfected individuals in the era of effective antiretroviral (ARV) therapy.
Cross-sectional study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort and controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study.
CRP levels were measured in 1135 HIV-infected participants from the FRAM cohort and 281 controls from the CARDIA study. The associations of HIV and HIV/HCV infection with CRP levels were estimated by multivariable linear regression.
Compared with controls, HIV monoinfection was associated with an 88% higher CRP level in men (P < 0.0001) but with no difference in women (5%; P = 0.80) in multivariate analysis. CRP levels were not associated with ARV therapy, HIV RNA level, or CD4 cell count. Compared with controls, HIV/HCV coinfection was associated with a 41% lower CRP level in women (P = 0.012) but with no difference in men (+4%; P = 0.90). Among HIV-infected participants, HCV coinfection was associated with 50% lower CRP levels after multivariable analysis (P < 0.0001) in men and women. Greater visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were strongly associated with CRP levels. Among HIV- infected participants, CRP levels were 17% (P < 0.001) and 21% (P = 0.002) higher per doubling of VAT and SAT; among controls, CRP levels were 34% (P < 0.001) and 61% (P = 0.009) higher, respectively.
In the absence of HCV coinfection, HIV infection is associated with higher CRP levels in men. HCV coinfection is associated with lower CRP levels in men and women.
cardiovascular disease; C-reactive protein; hepatitis C virus; HIV; inflammation
Studies in persons without HIV infection have compared percentage body fat (%BF) and waist circumference as markers of risk for the complications of excess adiposity, but only limited study has been conducted in HIV-infected subjects.
We compared anthropometric and magnetic resonance imaging (MRI)–based adiposity measures as correlates of metabolic complications of adiposity in HIV-infected and control subjects.
The study was a cross-sectional analysis of 666 HIV-positive and 242 control subjects in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study assessing body mass index (BMI), waist (WC) and hip (HC) circumferences, waist-to-hip ratio (WHR), %BF, and MRI-measured regional adipose tissue. Study outcomes were 3 metabolic risk variables [homeostatic model assessment (HOMA), triglycerides, and HDL cholesterol]. Analyses were stratified by sex and HIV status and adjusted for demographic, lifestyle, and HIV-related factors.
In HIV-infected and control subjects, univariate associations with HOMA, triglycerides, and HDL were strongest for WC, MRI-measured visceral adipose tissue, and WHR; in all cases, differences in correlation between the strongest measures for each outcome were small (r ≤ 0.07). Multivariate adjustment found no significant difference for optimally fitting models between the use of anthropometric and MRI measures, and the magnitudes of differences were small (adjusted R2 ≤ 0.06). For HOMA and HDL, WC appeared to be the best anthropometric correlate of metabolic complications, whereas, for triglycerides, the best was WHR.
Relations of simple anthropometric measures with HOMA, triglycerides, and HDL cholesterol are approximately as strong as MRI-measured whole-body adipose tissue depots in both HIV-infected and control subjects.
Both sagittal abdominal diameter (SAD) and waist circumference (WC) highly correlate with visceral adipose tissue (VAT) being linked to an atherogenic lipoprotein profile. However, it is uncertain whether SAD is a better correlate of atherogenic lipoprotein subfractions than WC. We examined relative associations of SAD versus WC with lipoprotein subfractions for U.S. white and Japanese men, concurrently examining the associations of VAT versus subcutaneous adipose tissue (SAT) with lipoprotein subfractions.
A population-based sample of 260 white and 282 Japanese men aged 40–49 was examined for VAT and SAT by computed tomography, SAD and WC by a portable sliding-beam caliper and a measuring tape, respectively, and lipoprotein subfractions by nuclear magnetic resonance spectroscopy.
Both SAD and WC were significantly and positively associated with large VLDL and total and small LDL particle concentrations, and inversely associated with large HDL particle concentration for both white and Japanese men. In BMI-adjusted regression models, the significant associations of SAD remained for both white and Japanese men, whereas those of WC became non-significant for white men. When SAD and WC were simultaneously included into the BMI-adjusted models, the associations of SAD remained significant and statistically stronger than those WC for both white and Japanese men. Furthermore, the pattern of the associations of SAD with those lipoprotein subfractions showed comparable to that of the associations of VAT.
SAD showed comparable to VAT and stronger than WC in the associations with atherogenic lipoprotein subfractions for middle aged, nondiabetic, white and Japanese men.
adiposity; intra-abdominal fat; abdominal subcutaneous fat; sagittal abdominal diameter; waist circumference; lipoproteins
Adiponectin is reduced in obesity, and has been suggested to play an important role in modulation of atherosclerosis. We studied the relationship between visceral (VAT) and subcutaneous (SAT) adipose tissue and serum adiponectin concentrations in Japanese men. Participants were 304 randomly selected community-based Japanese men aged 40 to 49 without a prior history of cardiovascular disease. Participants were grouped according to tertiles of serum adiponectin. In multiple linear regression analysis including age, pack years of smoking, and alcohol intake as covariates, log-transformed adiponectin was inversely associated with both VAT and SAT when these two obesity measures were included separately in the models. However, log-transformed adiponectin was inversely associated with VAT (standardized β estimate= −0.465, P< 0.0001) and positively associated with SAT (standardized β estimate = 0.166, P=0.03), when these were included concomitantly in the model. In conclusion, VAT and SAT had differential associations with serum adiponectin concentrations.
Increased cardiovascular risk has been linked to HIV infection and combination antiretroviral therapy, but the impact of hepatitis C virus (HCV) status on indices of cardiovascular risk has not been routinely assessed in the HIV-infected population. The objective of this study was to analyze associations of HCV, HIV, and combination antiretroviral therapy with lipid levels and C-reactive protein (CRP) among older men. We measured fasting total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride, and high-sensitivity CRP serum levels in a cross-sectional study of 108 HIV-infected and 74 HIV-uninfected at-risk older men. One hundred ten men (60%) had detectable HCV RNA, with no difference by HIV status (p = 0.25). The majority (88%) of men with HCV infection had a history of injection drug use. Among all men, HCV infection was independently associated with lower total cholesterol (p < 0.001), LDL-C (p < 0.001), triglycerides (p = 0.01), and CRP (p < 0.001). Among HIV-infected men, HCV infection was associated with lower total cholesterol (p < 0.001), LDL-C (p < 0.001), and CRP (p = 0.004). HCV infection was associated with lower triglycerides among men on protease inhibitors (PI) (p = 0.02) and non-PI combination antiretroviral therapy (p = 0.02), but not among antiretroviral-naïve men. These findings demonstrate an association of lower serum lipid and CRP levels with HCV infection and suggest that HCV status should be assessed as an important correlate of cardiovascular risk factors in studies of older men with or at risk for HIV.
Adipose tissue lipid storage and processing capacity can be a key factor for obesity-related metabolic disorders such as insulin resistance and diabetes. Lipid uptake is the first step to adipose tissue lipid storage. The aim of this study was to analyze the gene expression of factors involved in lipid uptake and processing in subcutaneous (SAT) and visceral (VAT) adipose tissue according to body mass index (BMI) and the degree of insulin resistance (IR).
Methods and Principal Findings
VLDL receptor (VLDLR), lipoprotein lipase (LPL), acylation stimulating protein (ASP), LDL receptor-related protein 1 (LRP1) and fatty acid binding protein 4 (FABP4) gene expression was measured in VAT and SAT from 28 morbidly obese patients with Type 2 Diabetes Mellitus (T2DM) or high IR, 10 morbidly obese patients with low IR, 10 obese patients with low IR and 12 lean healthy controls. LPL, FABP4, LRP1 and ASP expression in VAT was higher in lean controls. In SAT, LPL and FABP4 expression were also higher in lean controls. BMI, plasma insulin levels and HOMA-IR correlated negatively with LPL expression in both VAT and SAT as well as with FABP4 expression in VAT. FABP4 gene expression in SAT correlated inversely with BMI and HOMA-IR. However, multiple regression analysis showed that BMI was the main variable contributing to LPL and FABP4 gene expression in both VAT and SAT.
Morbidly obese patients have a lower gene expression of factors related with lipid uptake and processing in comparison with healthy lean persons.
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1×10E-09), previously identified in association with waist–hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9×10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6×10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. We quantified subcutaneous and visceral fat in more than 10,000 women and men who also had genome-wide association data available. Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, near the THNSL2 gene. These findings were not observed in men. We also interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed for 7 of these loci, most notably for VAT/SAT ratio. We conclude that genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not uncovered in large-scale GWAS of anthropometric traits.
The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM), initiated in 2000, investigates the prevalence and correlates of changes in fat distribution, insulin resistance, and dyslipidemia among human immunodeficiency virus (HIV)-infected men and women compared with a population-based group of control men and women. Between June 2000 and September 2002, 1,480 participants (1,183 HIV-infected persons and 297 controls) were enrolled in FRAM. Measurements taken included whole-body magnetic resonance imaging for quantification of regional fat, anthropometric measurements, central laboratory analysis of metabolites, and assessment of symptoms, sociodemographic factors, and lifestyle. Similar measurements were repeated among FRAM participants 4 years later (FRAM 2) for investigation of the progression of fat distribution changes, insulin resistance, and hyperlipidemia. In FRAM 2, which is ongoing, investigators are also determining the associations of subclinical cardiovascular disease, as measured by carotid intimal-medial wall thickness, with HIV infection, fat distribution changes, insulin resistance, and other proatherogenic changes in serum lipid levels. The demographic characteristics of HIV-infected FRAM men and women were comparable to those reported from a national random sampling of HIV-infected men and women receiving medical care in the United States. The representativeness of the FRAM sample increases its value as a resource for studies on fat distribution, metabolic changes, and atherosclerosis in HIV infection.
body fat distribution; dyslipidemias; HIV infections; insulin resistance; lipodystrophy; metabolism
Accumulation of adipose tissue is associated with cardiometabolic risks. Although visceral adipose tissue (VAT) has been strongly implicated in this relationship, there is still some debate regarding the contribution of abdominal subcutaneous adipose tissue (SAT). The purpose of this study was to determine the contribution of abdominal SAT to cardiometabolic risk factors, independent of total and visceral adiposity. These relationships were assessed in Caucasian and African Americans.
It is a cross-sectional analysis of the Pennington Center Longitudinal Study.
Data were extracted from 1246 participants. Total body fat mass (FM) was measured by dual-energy X-ray absorptiometry, whereas abdominal VAT and SAT areas (cm2) were measured with computed tomography. The cardiometabolic risk factors included resting blood pressure (BP), fasting blood glucose and triglyceride concentrations and high-density lipoprotein cholesterol (HDL-C).
Positive relationships across tertiles of VAT were seen for the participants with high glucose, high BP and low HDL-C (P<0.043). There was also a significant increase in the percentage of participants with two or more cardiometabolic risk factors across most tertiles of abdominal SAT (P<0.042). Logistic regression analysis showed that in univariate models, all adiposity measures were significantly associated with increased odds of having all risk factors in men and women. In multivariate models, VAT was significantly associated with most risk factors across gender. Abdominal SAT and FM (odds ratios (ORs) 1.3–2.1; all P<0.05) were associated with fewer risk factors after accounting for VAT. VAT (OR=5.9 and 5.3) and SAT (OR=2.0 and 1.8) were both associated with higher odds of the presence of two or more cardiometabolic risk factors in both males and females (P<0.001).
The data suggest that abdominal SAT is not protective against unfavorable cardiometabolic risk profiles. These conclusions were consistent across ethnic groups.
abdominal fat distribution; heart disease risk; epidemiology; ethnic differences
HIV-infected patients have metabolic abnormalities that put them at increased risk of cardiovascular disease (CVD), including abnormalities associated with HIV infection itself, antiretroviral treatment, restoration to health, and body composition changes. The 2 major components of dyslipidemia in HIV-infected patients are hypertriglyceridemia and reduction in high-density lipoprotein (HDL) cholesterol (with likely altered function of HDL cholesterol); these abnormalities contribute to increased atherosclerotic risk. Adverse effects of antiretroviral drugs on lipids are not class specific but rather are associated with particular drugs. Thus, practitioners need to be cognizant of the risks of metabolic abnormalities posed by individual drugs. HIV infection increases CVD risk independent of the effects of traditional risk factors. The relative risk of CVD in HIV-infected patients has decreased in recent years with increasing use of lipid-lowering therapy. However, use of lipid-lowering therapy is complicated by numerous potential drug interactions with antiretroviral drugs that practitioners need to consider when prescribing lipid-lowering therapy. This article summarizes a presentation made by Carl Grunfeld, MD, PhD, at the International AIDS Society–USA continuing medical education program in Los Angeles in March 2010. The original presentation is available as a Webcast at www.iasusa.org.
Adiponectin, paradoxically reduced in obesity and with lower levels in African Americans (AA), modulates several cardiometabolic risk factors. Because abdominal visceral adipose tissue (VAT), known to be reduced in AA, and subcutaneous adipose tissue (SAT) compartments may confer differential metabolic risk profiles, we investigated the associations of VAT and SAT with serum adiponectin, separately by gender, with the hypothesis that VAT is more strongly inversely associated with adiponectin than SAT.
Participants from the Jackson Heart Study, an ongoing cohort of AA (n = 2,799; 64% women; mean age, 55 ± 11 years) underwent computer tomography assessment of SAT and VAT volumes, and had stored serum specimens analyzed for adiponectin levels. These levels were examined by gender in relation to increments of VAT and SAT.
Compared to women, men had significantly lower mean levels of adiponectin (3.9 ± 3.0 μg/mL vs. 6.0 ± 4.4 μg/mL; p < 0.01) and mean volume of SAT (1,721 ± 803 cm3 vs. 2,668 ± 968 cm3; p < 0.01) but significantly higher mean volume of VAT (884 ± 416 cm3 vs. 801 ± 363 cm3; p < 0.01). Among women, a one standard deviation increment in VAT was inversely associated with adiponectin (β = − 0.13; p < 0.0001) after controlling for age, systolic blood pressure, fasting plasma glucose, high-density lipoprotein cholesterol, triglycerides, education, pack-years of smoking and daily intake of alcohol. The statistically significant inverse association of VAT and adiponectin persisted after additionally adjusting for SAT, body mass index (BMI) and waist circumference (WC), suggesting that VAT provides significant information above and beyond BMI and WC. Among men, after the same multivariable adjustment, there was a direct association of SAT and adiponectin (β = 0.18; p = 0.002) that persisted when controlling for BMI and WC, supporting a beneficial effect of SAT. Insulin resistance mediated the association of SAT with adiponectin in women.
In African Americans, abdominal visceral adipose tissue had an inverse association with serum adiponectin concentrations only among women. Abdominal subcutaneous adipose tissue appeared as a protective fat depot in men.