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1.  Fat Distribution in Women With HIV Infection 
Objective
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.
Methods
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.
Results
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.
Conclusions
Peripheral lipoatrophy occurs commonly in HIV-infected women but is not associated with reciprocally increased VAT or trunk fat.
doi:10.1097/01.qai.0000229996.75116.da
PMCID: PMC3166343  PMID: 16837863
HIV; lipodystrophy; lipoatrophy; lipohypertrophy; visceral obesity; fat redistribution; body composition
2.  Regional fat deposition and cardiovascular risk in HIV infection: The FRAM study 
AIDS care  2011;23(8):929-938.
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.
doi:10.1080/09540121.2010.543885
PMCID: PMC3249238  PMID: 21767228
HIV; fat redistribution; lipoatrophy; visceral fat; cardiovascular risk
3.  Intermuscular Adipose Tissue and Metabolic Associations in HIV Infection 
Obesity (Silver Spring, Md.)  2010;19(2):283-291.
Intermuscular adipose tissue (IMAT) is associated with metabolic abnormalities similar to those associated with visceral adipose tissue (VAT). Increased IMAT has been found in obese human immunodeficiency virus (HIV)-infected women. We hypothesized that IMAT, like VAT, would be similar or increased in HIV-infected persons compared with healthy controls, despite decreases in subcutaneous adipose tissue (SAT) found in HIV infection. In the second FRAM (Study of Fat Redistribution and Metabolic Change in HIV infection) exam, we studied 425 HIV-infected subjects and 211 controls (from the Coronary Artery Risk Development in Young Adults study) who had regional AT and skeletal muscle (SM) measured by magnetic resonance imaging (MRI). Multivariable linear regression identified factors associated with IMAT and its association with metabolites. Total IMAT was 51% lower in HIV-infected participants compared with controls (P = 0.003). The HIV effect was attenuated after multivariable adjustment (to −28%, P < 0.0001 in men and −3.6%, P = 0.70 in women). Higher quantities of leg SAT, upper-trunk SAT, and VAT were associated with higher IMAT in HIV-infected participants, with weaker associations in controls. Stavudine use was associated with lower IMAT and SAT, but showed little relationship with VAT. In multivariable analyses, regional IMAT was associated with insulin resistance and triglycerides (TGs). Contrary to expectation, IMAT is not increased in HIV infection; after controlling for demographics, lifestyle, VAT, SAT, and SM, HIV+ men have lower IMAT compared with controls, whereas values for women are similar. Stavudine exposure is associated with both decreased IMAT and SAT, suggesting that IMAT shares cellular origins with SAT.
doi:10.1038/oby.2010.115
PMCID: PMC3731045  PMID: 20539305
4.  Fat Distribution in Men With HIV Infection 
Objective
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.
Methods
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).
Results
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.
Conclusion
Both peripheral and central subcutaneous lipoatrophy was found in HIV infection. Lipoatrophy in HIV-positive men is not associated with reciprocally increased VAT.
PMCID: PMC3166344  PMID: 16186728
HIV infection; lipodystrophy; lipoatrophy; lipohypertrophy; visceral obesity; fat redistribution; body composition
5.  The Associations of Regional Adipose Tissue with Lipid and Lipoprotein Levels in HIV-infected Men 
Background
HIV infection and antiretroviral therapy are associated with dyslipidemia, but the association between regional adipose tissue depots and lipid levels is not defined.
Methods
The association of MRI-measured visceral (VAT) and regional subcutaneous adipose tissue (SAT) volume with fasting lipid parameters was analyzed by multivariable linear regression in 737 HIV-infected and 145 control men from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM).
Results
HIV-infected men had higher median triglycerides (TG) (170mg/dl vs. 107mg/dl, p<0.0001), lower high density lipoprotein (HDL-C) (38mg/dl vs. 46mg/dl, p<0.0001) and lower low density lipoprotein (LDL-C) (105mg/dl vs. 125mg/dl, p<0.0001) than controls. After adjustment, greater VAT was associated with higher TG and lower HDL-C in both HIV-infected and control men, while greater leg SAT was associated with lower TG in HIV-infected men with a similar trend in controls. More upper trunk SAT was associated with higher LDL-C and lower HDL-C in controls, while more lower trunk SAT was associated with higher TG in controls. After adjustment, HIV infection remained strongly associated (p<0.0001) with higher TG (+76%, CI: 53, 103), lower LDL-C (−19%, CI: −25,−12), and lower HDL-C (−18%, CI: −22,−12).
Conclusions
HIV-infected men are more likely than controls to have higher TG and lower HDL-C, which promote atherosclerosis, but also lower LDL-C. Less leg SAT and more VAT are important factors associated with high TG and low HDL-C in HIV-infected men. The reduced leg SAT in HIV-infected men with lipoatrophy places them at increased risk for pro-atherogenic dyslipidemia.
doi:10.1097/QAI.0b013e31816d9ba1
PMCID: PMC3156607  PMID: 18360291
6.  Insulin resistance, hepatic lipid and adipose tissue distribution in HIV infected men 
Antiviral therapy  2008;13(3):423-428.
Background
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.
Results
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.
Conclusion
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.
PMCID: PMC2871284  PMID: 18572755
liver fat; visceral adipose tissue; subcutaneous adipose tissue; inter-muscular adipose tissue; omental-mesenteric adipose tissue; retroperitoneal adipose tissue; HOMA; insulin resistance; HIV
7.  Regional Adipose Tissue and Elevations in Serum Aminotransferases in HIV-Infected Individuals 
Background
The association of fat distribution with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations is not well-defined in HIV-infected individuals. Obesity is associated with hepatic steatosis, and ALT is a marker of steatosis in the general population.
Methods
Cross-sectional analysis of 1119 HIV-infected and 284 control subjects. Hepatitis C virus (HCV) RNA testing determined HCV infection. Magnetic resonance imaging measured regional adipose tissue volume.
Results
After adjustment for demographic and lifestyle factors, visceral adipose tissue (VAT) was positively associated with ALT in HIV/HCV-coinfected subjects (+9.8%, 95% confidence interval [CI]: 2.8 to 17.6), HIV-monoinfected subjects (+8.0%, 95% CI: 4.2 to 12.1), and controls (+5.9%, 95% CI: 2.0 to 10.1). In contrast, lower trunk subcutaneous adipose tissue (SAT) was negatively associated with ALT in HIV/HCV-coinfected subjects (−14.3%, 95% CI: −24.7 to −4.2) and HIV-monoinfected subjects (−11.9%, 95% CI: −18.4 to −5.3); there was a trend toward an association in controls (−7.1%, 95% CI: −22.7 to 5.9). Estimated associations between regional adipose tissue and AST were small and did not reach statistical significance.
Conclusions
More VAT and less lower trunk SAT are associated with elevated ALT, which likely reflects the presence of steatosis. There was little association with AST. HCV infection and having more VAT or less lower trunk SAT are independently associated with elevated ALT in HIV infection. Study regarding the association between VAT, trunk SAT, HCV, and progression of steatosis and fibrosis is needed in HIV-infected individuals.
doi:10.1097/QAI.0b013e3181685700
PMCID: PMC2776053  PMID: 18285711
adipose tissue; aminotransferase levels; hepatitis C virus; HIV; lipodystrophy
8.  Gender differences in the association of visceral and subcutaneous adiposity with adiponectin in African Americans: the Jackson Heart Study 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2261-13-9
PMCID: PMC3586352  PMID: 23433085
9.  Association Between Hepatitis C Virus Coinfection and Regional Adipose Tissue Volume in HIV-Infected Men and Women 
Objective
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1097/QAI.0b013e3180423a95
PMCID: PMC3164885  PMID: 17356466
adipose tissue volume; fat distribution; hepatitis C virus; HIV; lipodystrophy
10.  Relationship of Abdominal Visceral and Subcutaneous Adipose Tissue With Lipoprotein Particle Number and Size in Type 2 Diabetes 
Diabetes  2008;57(8):2022-2027.
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.
doi:10.2337/db08-0157
PMCID: PMC2494673  PMID: 18469202
11.  Depot-specific regulation of glucose uptake and insulin sensitivity in HIV-lipodystrophy 
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.
doi:10.1152/ajpendo.00273.2005
PMCID: PMC3197775  PMID: 16131513
positron emission tomography; adipose tissue; insulin resistance; human immunodeficiency virus-lipodystrophy
12.  Genes Linked to Energy Metabolism and Immunoregulatory Mechanisms are Associated with Subcutaneous Adipose Tissue Distribution in HIV-infected Men 
Pharmacogenetics and genomics  2011;21(12):798-807.
Objective
Genetic studies may help explain abnormalities of fat distribution in HIV-infected patients treated with antiretroviral therapy (ARV).
Methods
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.
Results
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).
Conclusions
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.
doi:10.1097/FPC.0b013e32834b68f9
PMCID: PMC3210910  PMID: 21897333
HIV; HAART; GWAS; Subcutaneous Fat; SAT
13.  Waist to hip ratio and trunk to extremity fat (DXA) are better surrogates for IMCL and for visceral fat respectively than for subcutaneous fat in adolescent girls 
Background
Increased visceral adipose tissue (VAT) and intramyocellular lipids (IMCL) are associated with increased metabolic risk. Clinical and DXA body composition measures that are associated with VAT are generally even more strongly associated with subcutaneous adipose tissue (SAT) reflecting general adiposity, and thus are not specific for VAT. Measures more strongly associated with VAT than SAT (thus more specific for VAT), and predictors of IMCL have not been reported.
Subjects/Methods
We studied 30 girls 12-18 years; 15 obese, 15 normal-weight. The following were assessed: (1) anthropometric measures: waist circumference at the umbilicus and iliac crest (WC-UC and WC-IC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), (2) DXA measures: total fat, percent body fat (PBF), percent trunk fat (PTF), trunk-to-extremity fat ratio (TEFR), (3) MRI and 1H-MRS: VAT and SAT (L4-L5), soleus-IMCL.
Results
Group as a whole: WC, trunk fat and PBF were more strongly associated with SAT than VAT; none were specific for VAT. In contrast, PTF and TEFR were more significantly associated with VAT (r = 0.83 and 0.81 respectively, p <0.0001 for both) than SAT (r = 0.77 and 0.75, p < 0.0001 for both). Strongest associations of S-IMCL were with WHR (r = 0.66, p = 0.0004). Subgroup analysis: In obese girls, WHR and WHtR were more strongly correlated with VAT (r = 0.62 and 0.82, p = 0.04 and 0.001) than SAT (r = 0.41 and 0.73, p not significant and 0.007), and for DXA measures, PTF and TEFR were more significantly associated with VAT (r = 0.70 and 0.72, p = 0.007 and 0.006) than SAT (r = 0.52 and 0.53, p = 0.07 and 0.06). In controls, PTF and TEFR were more strongly correlated with VAT (r = 0.79, p = 0.0004 for both) than SAT (r = 0.71 and 0.72, p = 0.003 for both). WHR was associated with IMCL in obese girls (r = 0.78, p = 0.008), but not controls.
Conclusion
Overall, WHR (anthropometry), and PTF and TEFR (DXA) are good surrogates for IMCL and for visceral fat respectively in adolescent girls.
doi:10.1186/1743-7075-7-86
PMCID: PMC3018385  PMID: 21143876
14.  Association of HIV Infection and HIV/HCV Coinfection With C-Reactive Protein Levels 
Objective
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.
Design
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/QAI.0b013e3181685727
PMCID: PMC2561207  PMID: 18344877
cardiovascular disease; C-reactive protein; hepatitis C virus; HIV; inflammation
15.  Abdominal Myosteatosis is Independently Associated to Hyperinsulinemia and Insulin Resistance among Older Men without Diabetes 
Obesity (Silver Spring, Md.)  2013;21(10):2118-2125.
Design and Methods
Skeletal muscle adipose tissue (AT) infiltration (myosteatosis) increases with aging and may contribute to the development of type 2 diabetes mellitus (T2DM). It remains unclear if myosteatosis is associated to glucose and insulin homeostasis independent of total and central adiposity. We evaluated the association between intermuscular AT (IMAT) in the abdominal skeletal muscles (total, paraspinal and psoas) and fasting serum glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) in 393 non-diabetic Caucasian men aged 65+. Abdominal IMAT, visceral (VAT) and subcutaneous (SAT) AT (cm3) were measured by quantitative computed tomography at the L4-L5 intervertebral space.
Results
In age, study site, height and muscle volume adjusted regression analyses, total abdominal and psoas (but not paraspinal) IMAT were positively associated with glucose, insulin and HOMA-IR (all P < 0.003). The associations between total abdominal and psoas IMAT and insulin and HOMA-IR remained significant after further adjusting for lifestyle factors, as well as DXA total body fat, VAT or SAT in separate models (all P <0.009).
Conclusions
Our study indicates a previously unreported, independent association between abdominal myosteatosis and hyperinsulinemia and insulin resistance among older Caucasian men. These associations may be specific for particular abdominal muscle depots, illustrating the potential importance of separately studying specific muscle groups.
doi:10.1002/oby.20346
PMCID: PMC3661705  PMID: 23408772
Myosteatosis; intermuscular fat; skeletal muscle; fat distribution; insulin; insulin resistance
16.  Independent associations of insulin resistance with high whole-body intermuscular and low leg subcutaneous adipose tissue distribution in obese HIV-infected women123 
Background
Obesity and insulin resistance are growing problems in HIV-positive (HIV+) women receiving highly active antiretroviral therapy (HAART).
Objective
The objective was to determine the contribution of adipose tissue (AT) enlargement and distribution to the presence of insulin resistance in obese HIV+ women.
Design
Whole-body intermuscular AT (IMAT), visceral AT (VAT), subcutaneous AT (SAT), and SAT distribution (leg versus upper body) were measured by whole-body magnetic resonance imaging. Insulin sensitivity (SI) was measured with an intravenous glucose tolerance test in obese HIV+ women recruited because of their desire to lose weight (n = 17) and in obese healthy controls (n = 32).
Results
The HIV+ women had relatively less whole-body SAT and more VAT and IMAT than did the controls (P < 0.05 for all). A significant interaction by HIV status was observed for the relation of total SAT with SI (P < 0.001 for the regression’s slope interactions after adjustment for age, height, and weight). However, relations of IMAT, VAT, and SAT distribution (leg SAT as a percentage of total SAT; leg SAT%) with SI did not differ significantly between groups. For both groups combined, the best model predicting a low SI included significant contributions by both high IMAT and low leg SAT%, independent of age, height, and weight, and no interaction between groups was observed (overall r2 = 0.44, P = 0.0003).
Conclusion
In obese HIV+ women, high whole-body IMAT and low leg SAT% distribution are independently associated with insulin resistance.
PMCID: PMC2670485  PMID: 17616768
Subcutaneous adipose tissue; intermuscular adipose tissue; adipose tissue distribution; insulin resistance; HIV infection
17.  Association of Increased Upper Trunk and Decreased Leg Fat With 2-h Glucose in Control and HIV-Infected Persons 
Diabetes Care  2011;34(11):2448-2453.
OBJECTIVE
Changes in body fat distribution and abnormal glucose metabolism are common in HIV-infected patients. We hypothesized that HIV-infected participants would have a higher prevalence of impaired glucose tolerance (IGT) compared with control subjects.
RESEARCH DESIGN AND METHODS
A total of 491 HIV-infected and 187 control participants from the second examination of the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) underwent glucose tolerance testing (GTT). Multivariable regression was used to identify factors associated with GTT parameters.
RESULTS
The prevalence of impaired fasting glucose (IFG) (>110 mg/dL) was similar in HIV-infected and control participants (21 vs. 25%, P = 0.23). In those without IFG, the prevalence of IGT was slightly higher in HIV-infected participants compared with control subjects (13.1 vs. 8.2%, P = 0.14) and in HIV+ participants with lipoatrophy versus without (18.1 vs. 11.5%, P = 0.084). Diabetes detected by GTT was rare (HIV subjects 1.3% and control subjects 0%, P = 0.65). Mean 2-h glucose levels were 7.6 mg/dL higher in the HIV-infected participants (P = 0.012). Increased upper trunk subcutaneous adipose tissue (SAT) and decreased leg SAT were associated with 2-h glucose and IGT in both HIV-infected and control participants. Adjusting for adipose tissue reduced the estimated effects of HIV. Exercise, alcohol use, and current tenofovir use were associated with lower 2-h glucose levels in HIV-infected participants.
CONCLUSIONS
In HIV infection, increased upper trunk SAT and decreased leg SAT are associated with higher 2-h glucose. These body fat characteristics may identify HIV-infected patients with normal fasting glucose but nonetheless at increased risk for diabetes.
doi:10.2337/dc11-0616
PMCID: PMC3198295  PMID: 21926283
18.  The ratio of visceral to subcutaneous fat, a metric of body fat distribution, is a unique correlate of cardiometabolic risk 
Diabetologia  2012;55(10):2622-2630.
Aims/hypothesis
The anatomic location of excess body fat has an impact on associated cardiometabolic morbidity, and visceral adipose tissue (VAT) is more pathogenic than subcutaneous adipose tissue (SAT). However, VAT or SAT alone provides little information regarding the relative distribution of body fat. We hypothesised that the propensity to store energy in VAT relative to SAT depots may be a correlate of cardiometabolic risk, and tested this hypothesis using the VAT/SAT ratio as a metric of fat distribution.
Methods
We investigated associations of the VAT/SAT ratio with cardiometabolic traits in 3,223 participants (48% women) from the Framingham Heart Study. Fat depots were quantified by multidetector computed tomography (CT) scanning.
Results
In women and men, higher VAT/SAT ratio was associated (p<0.05) with most assessed cardiovascular risk factors reflecting blood pressure, dyslipidaemia and insulin resistance. Additional adjustment for BMI did not materially change the findings in women, and generally strengthened associations in men. Further adjustment for VAT attenuated some associations in women, but those with lower HDL-cholesterol, higher triacylglycerol (both p<0.0001) and higher prevalence of hypertension (p=0.02), diabetes (p=0.01) and the metabolic syndrome (p=0.005) remained significant. Similarly, in men, associations with higher systolic (p=0.006) and diastolic blood pressure (p=0.03), higher fasting glucose (p=0.0005), lower HDL-cholesterol and higher triacylglycerol (both p<0.0001) and higher prevalence of diabetes (p=0.006) remained significant.
Conclusions/interpretation
VAT/SAT ratio is a correlate of cardiometabolic risk, above and beyond BMI and VAT. The propensity to store fat viscerally versus subcutaneously may be a unique risk factor independent of absolute fat volumes.
doi:10.1007/s00125-012-2639-5
PMCID: PMC3636065  PMID: 22898763
Body fat distribution; Obesity; Risk factors; Subcutaneous fat; Visceral fat
19.  Abdominal Subcutaneous and Visceral Adipose Tissue and Insulin Resistance in the Framingham Heart Study 
Obesity (Silver Spring, Md.)  2010;18(11):2191-2198.
Insulin resistance is associated with central obesity and an increased risk of cardiovascular disease. Our objective is to examine the association between abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) and insulin resistance, to determine which fat depot is a stronger correlate of insulin resistance, and to assess whether there was an interaction between SAT, VAT, and age, sex, or BMI. Participants without diabetes from the Framingham Heart Study (FHS), who underwent multidetector computed tomography to assess SAT and VAT (n = 3,093; 48% women; mean age 50.4 years; mean BMI 27.6 kg/m2), were evaluated. Insulin resistance was measured using the homeostasis model and defined as HOMAIR ≥75th percentile. Logistic regression models, adjusted for age, sex, smoking, alcohol, menopausal status, and hormone replacement therapy use, were used to assess the association between fat measures and insulin resistance. The odds ratio (OR) for insulin resistance per standard deviation increase in SAT was 2.5 (95% confidence interval (CI): 2.2–2.7; P < 0.0001), whereas the OR for insulin resistance per standard deviation increase in VAT was 3.5 (95% CI: 3.1–3.9; P < 0.0001). Overall, VAT was a stronger correlate of insulin resistance than SAT (P < 0.0001 for SAT vs. VAT comparison). After adjustment for BMI, the OR of insulin resistance for VAT was 2.2 (95% CI: 1.9–2.5; P < 0.0001). We observed an interaction between VAT and BMI for insulin (P interaction = 0.0004), proinsulin (P interaction = 0.003), and HOMAIR (P interaction = 0.003), 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.
doi:10.1038/oby.2010.59
PMCID: PMC3033570  PMID: 20339361
20.  Visceral and subcutaneous adipose tissue from lean women respond differently to lipopolysaccharide-induced alteration of inflammation and glyceroneogenesis 
Nutrition & Diabetes  2012;2(12):e51-.
Objective:
Experimental endotoxaemia induces subcutaneous adipose tissue inflammation and systemic insulin resistance in lean subjects. Glyceroneogenesis, by limiting free fatty acids (FFA) release from adipocytes, controls FFA homoeostasis and systemic insulin sensitivity. The roles of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in metabolic deregulation are intrinsically different. We compared the effect of lipopolysaccharide (LPS) on the inflammation profiles of SAT and VAT explants from lean women, as well as on glyceroneogenesis, to test whether these two fat depots have intrinsically different responses to this metabolic endotoxin.
Design:
Abdominal SAT and VAT explants from eight lean women were treated in vitro with LPS. Their inflammatory status was evaluated by cytokine gene expression and secretion; glyceroneogenesis was evaluated by cytosolic phosphoenolpyruvate carboxykinase activity and FFA vs glycerol release.
Results:
In the basal state, the cytokine status and expression of macrophage markers were lower in SAT than VAT. In the presence of 100 ng ml−1 LPS, SAT exhibited a strong inflammatory response (increased interleukin-6 and tumor necrosis factor-α expression) and increased release of FFA due to inhibition of glyceroneogenesis, whereas VAT was only mildly affected. The effects of LPS on both tissues were blocked by the nuclear factor-κB (NF-κB) inhibitor, parthenolide. A significant effect of LPS on VAT occurred only at 1 μg ml−1 LPS.
Conclusion:
SAT explants from lean women are more sensitive to LPS-induced NF-κB activation than are VAT explants, leading to a depot-specific dysfunction of FFA storage. As SAT is the major player in FFA homoeostasis, this SAT dysfunction could be associated with visceral fat hypertrophy and systemic lipid disorders.
doi:10.1038/nutd.2012.29
PMCID: PMC3542433  PMID: 23208412
subcutaneous adipose tissue; visceral adipose tissue; lean human; LPS; inflammation; glyceroneogenesis
21.  Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults 
Obesity (Silver Spring, Md.)  2013;21(9):E439-E447.
Visceral (VAT) and abdominal subcutaneous (SAT) adipose tissues contribute to obesity but may have different metabolic and atherosclerosis risk profiles. 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. 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. In 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.
doi:10.1002/oby.20135
PMCID: PMC3751977  PMID: 23687099
Obesity; Lipoproteins; Inflammation; Atherosclerosis; Diabetes
22.  Increased FDG uptake in Association with Reduced Extremity Fat in HIV Patients 
Antiviral therapy  2012;18(2):243-248.
Background/Objective
HIV lipodystrophy - characterized by peripheral lipoatrophy, with or without central fat accumulation - confers increased metabolic risk. However, the functional activity of HIV lipodystrophic tissue in relation to metabolic risk has yet to be fully explored in vivo through the use of non-invasive imaging techniques. This study assesses the relationship between FDG uptake in various fat depots and metabolic/immune parameters among subjects with HIV lipodystrophy.
Design/Methods
Lipodystrophic men on anti-retroviral therapy (ART) underwent whole-body 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) scans and detailed metabolic/immune phenotyping.
Results
FDG uptake in the subcutaneous adipose tissue (SAT) of the extremities (mean standardized uptake value, or SUV, of the arm and leg SAT) was found to correlate with the degree of peripheral lipoatrophy (r = 0.7, p = 0.01). Extremity SAT FDG uptake was positively associated with HOMA-IR (r = 0.6, p = 0.02) and fasting hyperinsulinemia (r = 0.7, p 0.01), while fat percentage of extremities was not. Further, extremity SAT FDG uptake was significantly associated with CD4 count (r = 0.6, p = 0.05). In multivariate modeling for HOMA-IR, extremity SAT FDG uptake remained significant after controlling for BMI and TNF-α (R2 for model = 0.71, p = 0.02; SUV in the extremity SAT β-estimate 12.3, p = 0.009).
Conclusions
In HIV lipodystrophic patients, extremity SAT FDG uptake is increased in association with reduced extremity fat and may contribute to insulin resistance. Noninvasive assessments of in situ inflammation using FDG-PET may usefully complement histological and gene expression analyses of metabolic dysregulation in peripheral fat among HIV+ patients.
doi:10.3851/IMP2420
PMCID: PMC3670757  PMID: 23041595
HIV; lipodystrophy; FDG-PET/CT; insulin resistance
23.  Simple anthropometric measures correlate with metabolic risk indicators as strongly as magnetic resonance imaging–measured adipose tissue depots in both HIV-infected and control subjects2 
Background
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.
Objective
We compared anthropometric and magnetic resonance imaging (MRI)–based adiposity measures as correlates of metabolic complications of adiposity in HIV-infected and control subjects.
Design
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.
Results
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.
Conclusion
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.
PMCID: PMC2587301  PMID: 18541572
24.  Regional Adipose Tissue and Lipid and Lipoprotein Levels in HIV-Infected Women 
Background
HIV infection and antiretroviral therapy are associated with dyslipidemia, but the association between regional body fat and lipid levels is not well described.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1097/QAI.0b013e318164227f
PMCID: PMC2776070  PMID: 18197118
dyslipidemia; fat distribution; HIV infection; lipid levels; lipodystrophy; women
25.  Differential Intra-abdominal Adipose Tissue Profiling in Obese, Insulin-resistant Women 
Obesity surgery  2009;19(11):1564-1573.
Background
We recently identified differences in abdominal subcutaneous adipose tissue (SAT) from insulin-resistant (IR) as compared to obesity-matched insulin sensitive individuals, including accumulation of small adipose cells, decreased expression of cell differentiation markers, and increased inflammatory activity. This study was initiated to see if these changes in SAT of IR individuals were present in omental visceral adipose tissue (VAT); in this instance, individuals were chosen to be IR but varied in degree of adiposity. We compared cell size distribution and genetic markers in SAT and VAT of IR individuals undergoing bariatric surgery.
Methods
Eleven obese/morbidly obese women were IR by the insulin suppression test. Adipose tissue surgical samples were fixed in osmium tetroxide for cell size analysis via Beckman Coulter Multisizer. Quantitative real-time polymerase chain reaction for genes related to adipocyte differentiation and inflammation was performed.
Results
While proportion of small cells and expression of adipocyte differentiation genes did not differ between depots, inflammatory genes were upregulated in VAT. Diameter of SAT large cells correlated highly with increasing proportion of small cells in both SAT and VAT (r=0.85, p= 0.001; r=0.72, p=0.01, respectively). No associations were observed between VAT large cells and cell size variables in either depot. The effect of body mass index (BMI) on any variables in both depots was negligible.
Conclusions
The major differential property of VAT of IR women is increased inflammatory activity, independent of BMI. The association of SAT adipocyte hypertrophy with hyperplasia in both depots suggests a primary role SAT may have in regulating regional fat storage.
doi:10.1007/s11695-009-9949-9
PMCID: PMC3181138  PMID: 19711137
Adipose cell size; Inflammation; Obesity; Visceral adipose tissue

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