Both fatty liver and abdominal visceral fat (VAT) are associated with cardiometabolic risk factors. Whether fatty liver and VAT are jointly associated with coronary artery (CAC) or abdominal aortic (AAC) calcification is not clear.
Jackson Heart Study (JHS) participants (n=2884, mean age 60 years, 65% women) underwent non-contrast CT Exam for assessment of fatty liver, VAT, and CAC and AAC. Fatty liver was measured by liver attenuation (LA; low LA=high fatty liver). The Agatston score was used to quantify the amount of calcified artery plaque and the presence of calcified artery plaque was defined as Agatston score>0. Cross-sectional associations of LA and VAT with CAC and AAC were examined in logistic regression models.
LA (per 1-standard deviation [SD] decrement) was associated inversely with CAC in age-sex-adjusted (OR 0.84, 95%CI 0.7–0.9, p=0.0001) and multivariable adjusted models (OR 0.89, 95%CI 0.8–0.9, p=0.01). The association persisted for LA with CAC when additionally adjusted for body mass index (BMI) (OR 0.89, 95%CI 0.8–0.9, p=0.03) or VAT (OR 0.90, 95%CI 0.8–0.9, p=0.04). Abdominal VAT (per 1-SD increment) was positively associated with CAC in age-sex-adjusted models (OR 1.27, 95%CI 1.2–1.4, p=0.0001), but the association was diminished with multivariable adjustment (OR 1.10, 95%CI 0.9–1.2, p=0.09) and with additional adjustment for LA (p = 0.24) or BMI (p = 0.33). For AAC, the associations with LA and VAT were only present in age-sex-adjusted models. Finally, we did not observe interactions between LA and VAT for CAC (p=0.18) or AAC (p=0.24).
Fatty liver is associated with coronary atherosclerotic calcification independent of abdominal VAT or BMI in African Americans. Further investigations to uncover the clinical implications of fatty liver on coronary atherosclerosis in obesity are warranted.
Black South African women are less insulin sensitive than their white counterparts, despite less central and greater peripheral fat deposition. We hypothesized that this paradox may be explained, in part, by differences in the adipogenic capacity of subcutaneous adipose tissue (SAT).
To measure adipogenic and lipogenic gene expression in abdominal and gluteal SAT depots, and determine their relationships with insulin sensitivity (SI) in South African women.
14 normal-weight (BMI <25 kg/m2) black, 13 normal-weight white, 14 obese (BMI >30 kg/m2) black and 13 obese white premenopausal South African women.
SI (frequently sampled intravenous glucose tolerance test) in relation to expression of adipogenic and lipogenic genes in abdominal and gluteal SAT depots.
With increasing BMI, black women had less visceral fat (P=0.03) and more abdominal (P=0.017) and gynoid (P=0.041) SAT but had lower SI (P<0.01) than white women. The expression of adipogenic and lipogenic genes was proportionately lower with obesity in black, but not white women in the gluteal and deep SAT depots (P<0.05 for ethnicity x BMI effect). In black women only, the expression of these genes correlated positively with SI (all P<0.05), independently of age and fat mass.
Obese black women have reduced SAT expression of adipogenic and lipogenic genes compared to white women, which associates with reduced SI. These findings suggest that obesity in black women impairs SAT adipogenesis and storage, potentially leading to insulin resistance and increased risk of type 2 diabetes.
insulin sensitivity; ethnicity; adipogenesis; lipogenesis; adipose tissue distribution; hypertrophic obesity
Burden of obesity has increased significantly in the United States over last few decades. Association of obesity with insulin resistance and related cardiometabolic problems is well established. Traditionally, adipose tissue in visceral fat depot has been considered a major culprit in development of insulin resistance. However, growing body of the literature has suggested that adipose tissue in subcutaneous fat depot, not only due to larger volume but also due to inherent functional characteristics, can have significant impact on development of insulin resistance. There are significant differences in functional characteristics of subcutaneous abdominal/truncal versus gluteofemoral depots. Decreased capacity for adipocyte differentiation and angiogenesis along with adipocyte hypertrophy can trigger vicious cycle of inflammation in subcutaneous adipose tissue and subsequent ectopic fat deposition. It is important to shift focus from fat content to functional heterogeneity in adipose tissue depots to better understand the relative role of subcutaneous adipose tissue in metabolic complications of obesity. Therapeutic lifestyle change continues to be the most important intervention in clinical practice at any level of increased adiposity. Future pharmaceutical interventions aimed at improving adipose tissue function in various subcutaneous depots have potential to help maintain adequate insulin sensitivity and reduce risk for development of insulin resistance complications.
Coronary artery calcified atherosclerotic plaque (CP) is strongly associated with nonsubcutaneous adipose tissue, particularly pericardial adipose tissue (PAT), in community-based studies. We tested for relationships between regional adipose tissue depots and CP in African Americans with longstanding type 2 diabetes. Infrarenal aorta, coronary, and carotid artery CP and pericardial, visceral, intermuscular, and subcutaneous organ-specific adipose tissue volumes were measured using single and multidetector computed tomography (CT) in 422 African Americans with type 2 diabetes. Generalized estimating equations using exchangeable correlation and the sandwich estimator of the variance were used to test for associations between CP and adipose tissue depots. Mean (s.d.) age was 56.5 (7.6) years, diabetes duration 10.3 (7.6) years, PAT 85.3 (36.1) cm3/45 mm and visceral adipose tissue (VAT) 174.9 (70.1) cm3/15 mm. Adjusting for age, gender, BMI, blood pressure, medications, proteinuria, smoking, lipids, and 25-hydroxyvitamin D, PAT was positively associated with the presence (P = 0.009) and quantity of coronary artery CP in African Americans (P = 0.004), as well as the quantity of infrarenal aorta CP (P = 0.004). As in European Americans, PAT is associated with CP in African Americans with type 2 diabetes. Ethnic differences in the relationships between organ-specific adipose tissue depots and atherosclerosis require further study.
Abdominal adiposity, especially visceral adiposity, is an emerging cardiometabolic risk factor. How abdominal fat is distributed in rheumatoid arthritis (RA) and its RA-related determinants have not been explored.
Men and women with RA were compared to non-RA controls from the Multi-Ethnic Study of Atherosclerosis. Participants underwent anthropometric measures and quantification of visceral and subcutaneous fat areas (VFA, SFA) using abdominal computed tomography.
A total of 131 RA patients were compared with 121 controls. Despite similar body mass index and waist circumference between the RA and control groups, the adjusted mean VFA was 45cm2 higher (+51%) for RA vs. control men (p=0.005) but not significantly different by RA status in women. The adjusted mean SFA was 119cm2 higher (+68%) for RA vs. control women (p<0.001) but not significantly different by RA status in men. Elevated VFA (>75th percentile) was associated with a significantly higher adjusted probability of having an elevated fasting glucose, hypertension, or the composite definition of the metabolic syndrome for the RA group compared with controls. Within the RA group, rheumatoid factor seropositivity and higher cumulative prednisone exposure were significantly associated with a higher mean adjusted VFA. Higher C-reactive protein levels and lower Sharp scores were significantly associated with both VFA and SFA.
The distribution of abdominal fat differs significantly by RA status. Higher VFA in men with RA, and the more potent association of VFA with cardiometabolic risk factors in men and women with RA, may contribute to cardiovascular risk in RA populations.
Atherosclerosis is the primary cause of coronary artery disease (CAD). There is increasing recognition that lesion composition rather than size determines the acute complications of atherosclerotic disease. Low serum adiponectin levels were reported to be associated with coronary artery disease and future incidence of acute coronary syndrome (ACS). The impact of adiponectin on lesion composition still remains to be determined.
We measured serum adiponectin levels in 303 patients with stable typical or atypical chest pain, who underwent dual-source multi-slice CT-angiography to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified. In bivariate analysis adiponectin levels were inversely correlated with total coronary plaque burden (r = −0.21, p = 0.0004), mixed (r = −0.20, p = 0.0007) and non-calcified plaques (r = −0.18, p = 0.003). No correlation was seen with calcified plaques (r = −0.05, p = 0.39). In a fully adjusted multivariate model adiponectin levels remained predictive of total plaque burden (estimate: −0.036, 95%CI: −0.052 to −0.020, p<0.0001), mixed (estimate: −0.087, 95%CI: −0.132 to −0.042, p = 0.0001) and non-calcified plaques (estimate: −0.076, 95%CI: −0.115 to −0.038, p = 0.0001). Adiponectin levels were not associated with calcified plaques (estimate: −0.021, 95% CI: −0.043 to −0.001, p = 0.06). Since the majority of coronary plaques was calcified, adiponectin levels account for only 3% of the variability in total plaque number. In contrast, adiponectin accounts for approximately 20% of the variability in mixed and non-calcified plaque burden.
Adiponectin levels predict mixed and non-calcified coronary atherosclerotic plaque burden. Low adiponectin levels may contribute to coronary plaque vulnerability and may thus play a role in the pathophysiology of ACS.
During the finishing phase of bovines, large amounts of subcutaneous and visceral fats are deposited leading to production inefficiencies with major impact on meat quality. A better understanding of the cellularity features of the main fat depots could provide strategies for adipose tissue manipulation. This study assessed the effect of feeding diets with distinct forage to concentrate ratios on the cellularity of two fat depots of beef cattle and their implications on the fatty acid profile. Thus, two phylogenetically distant Portuguese bovine breeds, Alentejana and Barrosã, were selected. The results did not show differences in subcutaneous fat deposition nor in visceral fat depots partitioning. Plasma adipokines concentration failed to show a consistent relationship with fatness, as leptin remained constant in all experimental groups, whereas interleukin-6 was influenced by breed. Fat depot seems to determine the area and number of adipocytes, with larger adipocytes and a lower number of cells in subcutaneous fat than in mesenteric fat. Neither breed nor diet influenced adipocytes area and number. The contents of total fatty acids, partial sums of fatty acids and conjugated linoleic acid isomeric profile were affected by breed and fat depot. The incorporation of saturated fatty acids (SFA), trans fatty acids, polyunsaturated fatty acids (PUFA) and branched chain fatty acids (BCFA) was higher in mesenteric fat depot, whereas subcutaneous fat depot had greater percentages of monounsaturated fatty acids (MUFA). In addition, SFA and MUFA proportions seem to be breed-related. In spite of the less relevant role of diet, the percentages of PUFA and BCFA were influenced by this factor. Under these experimental conditions, the effect of fat depot on cellularity and fatty acid composition prevails over breed or diet, as reinforced by the principal component analysis.
bovine; fat depots; cellularity; fatty acid composition; adipokines.
Carotid intima-media thickness (IMT) is a sub-clinical marker of atherosclerosis and a strong predictor of stroke. Pericardial fat (PF), the fat depot around the heart, has been associated with several atherosclerosis risk factors. We sought to examine the association between carotid IMT and PF, and to examine whether such an association is independent from common atherosclerosis risk factors including measures of overall adiposity.
Unadjusted and multivariable adjusted linear regression analysis was used to examine associations between common (CCA-IMT) and internal (ICA-IMT) carotid IMT with PF in a random sample of 996 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent carotid ultrasound and chest CT at baseline examination.
A significant positive correlation was observed between PF and CCA-IMT (r =0.27, P<0.0001) and ICA-IMT (r =0.17, P<0.0001). In an unadjusted sex-specific linear regression analysis, there was a significant association between PF (1-SD difference) and CCA-IMT (mm) in both women (β coefficient (95% CI): 0.06 (0.04, 0.08), P<0.0001) and men (0.03 (0.01, 0.05), P<0.0002), an association that persisted after further adjusting for age and ethnicity (0.02 (+0.00, 0.04), P=0.0120 for women, and 0.02 (+0.00, 0.03), P=0.0208 for men). However, after additional adjustment for atherosclerosis risk factors and either BMI or waist circumference, these relations were no longer significant in either sex. In similar analyses, PF was significantly associated with ICA-IMT in both men (0.11 (0.06, 0.15), P<0.0001) and women (0.08 (0.02, 0.13), P=041). These relations were no longer significant in women in multivariable adjusted models, but persisted in men in all models except after adjusting for age, ethnicity and waist circumference.
In the general population PF is associated with carotid IMT, an association that possibly not independent from markers of overall adiposity or common atherosclerosis risk factors.
The measurement of adipose tissue depots in-vivo requires expensive imaging methods not accessible to most clinicians and researchers. The study aim was to derive mathematical models to predict total adipose tissue (TAT) and sub-depots from total body fat derived from a dual energy x-ray absorptiometry (DXA) scan.
Models were developed to predict magnetic resonance imaging derived TAT and sub-depots subcutaneous (SAT), visceral (VAT), and intermuscular (IMAT) from DXA total body fat using cross-sectional data (T0) and validated results using 1 (T1) and 2 (T2) year follow-up data. Subjects were 176 multi-ethnic healthy children ages 5 to 17 years at T0. 22 were measured at T1 and T2. TAT was compared to fat.
At T0, TAT was greater than fat (12.5 ± 8.4 vs.12.0 ± 9.4 kg; p< 0.0001), with a quadratic relationship between TAT and fat which varied by sex. Predicted mean TAT’s were not different from measured TAT’s: T1: (9.84±4.45 kg vs. 9.50±4.37 kg; p=0.11) T2: (12.94±6.75 kg vs. 12.89±7.09 kg; p=0.76). The quadratic relationship was not influenced by race or age.
In general, the prediction equations for TAT and sub-depots were consistent with the measured values using T1 and T2 data.
This study considered the association between sexual maturation and adiposity in children and adolescents, and examined the contribution of sexual maturation to ethnic differences in total and depot-specific body fat.
The sample included 382 White and African American 5–18-year-olds. Body mass index (BMI), waist circumference (WC) and sexual maturity status (breast/genital and pubic hair stage) were assessed in a clinical setting. Total body fat (TBF) was measured by dual-energy X-ray absorptiometry and abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) were measured by magnetic resonance imaging. Analysis of covariance adjusted for age was used to examine the association between sexual maturity status and adiposity, and linear regression adjusted for age was used to examine the influence of sexual maturation on ethnic differences in adiposity. Analysis of VAT also controlled for TBF. Significance was accepted at P<0.05.
Breast/genital stage was significantly associated with BMI, WC, TBF, and SAT in girls of both ethnic groups and in White boys. Breast stage was associated with VAT. Stage of pubic hair was significantly associated with TBF and VAT in White girls only. In girls, sexual maturation attenuated the ethnic effects on BMI and WC, but the ethnic effect in VAT persisted. In boys, sexual maturation did not attenuate ethnic differences on VAT and did not predict WC or SAT. Sexual maturity status independently explained variance in adiposity in girls only.
Sexual maturity status is an important determinant of pediatric adiposity and attenuates ethnic differences in girls’ adiposity.
The aim of this study was to evaluate whether computed tomography (CT) attenuation, as a measure of fat quality, is associated with cardiometabolic risk factors above and beyond fat quantity.
Visceral (VAT) and subcutaneous adipose tissue (SAT) are pathogenic fat depots associated with cardiometabolic risk. Adipose tissue attenuation in CT images is variable, similar to adipose tissue volume. However, whether the quality of abdominal fat attenuation is associated to cardiometabolic risk independent of the quantity is uncertain.
Participants were drawn from the Framingham Heart Study CT sub-study. VAT and SAT volumes were acquired by semi-quantitative assessment. Fat quality was measured by CT attenuation and recorded as mean Hounsfield Units (HU) within each fat depot. Sex-specific linear and logistic multivariable regression models were used to assess the association between standard deviation (SD) decrease in HU and each risk factor.
Lower CT attenuation of VAT and SAT was correlated with higher BMI levels in both sexes. Risk factors were generally more adverse with decreasing HU values. For example, in women, per 1-SD decrease in VAT HU, the odds ratio (OR) was increased for hypertension (OR 1.80), impaired fasting glucose (OR 2.10), metabolic syndrome (OR 3.65) and insulin resistance (OR 3.36) (all p<0.0001). In models that further adjusted for VAT volume, impaired fasting glucose, metabolic syndrome and insulin resistance remained significant. Trends were similar but less pronounced in SAT and in men. There was evidence of an interaction between HU and fat volume among both women and men.
Lower CT attenuation of VAT and SAT is associated with adverse cardiometabolic risk above and beyond total adipose tissue volume. Qualitative indices of abdominal fat depots may provide insight regarding cardiometabolic risk independent of fat quantity.
Obesity; Epidemiology; CT Imaging; Risk Factors
This study examines intercorrelations among waist circumference (WC), intraperitoneal fat (IPF), and subcutaneous abdominal fat (SAF) in ethnically diverse Dallas Heart Study consisting of 1538 women and 1212 men (50% Black). Correlations between fat depots and triglyceride or HOMA2-IR, biomarkers of metabolic syndrome, are also reported. Total abdominal fat (TAF), ASF, and IPF masses were measured by magnetic resonance imaging. The highest correlations with WC according to ethnicity and gender were noted for TAF (R2 = 0.81 − 0.88) with progressively lower correlations with ASF (0.65–0.82) and IPF (0.29–0.85). The percentage of IPF relative to TAF was not significantly correlated with WC. For all WC categories, higher IPF/ASF ratios were associated with higher triglyceride levels. In contrast, differences in ratios had little or no association with HOMA2-IR. However, when all data were pooled, IPF was positively correlated with both triglyceride (r = 0.358 (men) and 0.363 (women)) and HOMA2-IR (r = 0.480 (men) and 0.517 (women)); after adjustment for ASF, IPF was still correlated with triglyceride (r = 0.353 (men) and 0.348 (women)) and HOMA2-IR (r = 0.290 (men) and 0.221 (women)). WC measures TAF reliably, but its association with IPF depends on IPF/ASF ratios that vary by gender and ethnicity.
Diacylglycerol acyltransferase (DGAT) could be a rate limiting step in triglyceride (TG) synthesis as it is the final step in this pathway. As such, between depot differences in DGAT activity could influence regional fat storage. DGAT activity and in vitro rates of direct free fatty acid (FFA) storage were measured in abdominal subcutaneous and omental adipose tissue samples from 12 non-obese (BMI < 30kg/m2) and 23 obese men and women (BMI > 30kg/m2) undergoing elective surgery. DGAT activity was greater in omental than in abdominal subcutaneous adipose tissue from non-obese patients (2.0 ± 0.9 vs. 0.9 ± 0.3 pmol/min/mg lipid, respectively, P = 0.003), but not from obese patients (1.4 ± 0.6 vs. 1.7 ± 0.7 pmol/min/mg lipid, respectively, P = 0.10). DGAT activity per unit adipose weight was negatively correlated with adipocyte size (p<0.01) and positively correlated with direct FFA storage in omental (p<0.001) but not in abdominal subcutaneous fat. Tissue DGAT activity varies as a function of adipocyte size, but this relationship differs between visceral and abdominal subcutaneous fat in obese and non-obese humans. Our results are consistent with the hypothesis that inter-individual variations in DGAT activity may be an important regulatory step in visceral adipose tissue FFA uptake/storage.
DGAT; FFA; triglyceride; regional fat; enzyme assay; body composition; adipocyte size
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.
Associations of epicardial fat volume (EFV) measured on non-contrast cardiac computed tomography (NCT) include coronary plaque, myocardial ischemia and adverse cardiac events.
This study aimed to define the relationship of EFV to coronary plaque type, severe coronary stenosis, and to the presence of high-risk plaque features (HRPFs).
We retrospectively evaluated 402 consecutive patients, with no prior history of coronary artery disease, who underwent same day non-contrast cardiac computed tomography (NCT) and coronary CT angiography (CTA). EFV was measured on NCT using validated, semi-automated, software. The coronary arteries were evaluated for coronary plaque type [calcified (CP), non-calcified (NCP) or partially-calcified (MP)] and coronary stenosis severity ≥70% using coronary CTA. For patients with NCP and PCP, 2 high risk plaque features were evaluated: Low-attenuation plaque and positive remodeling.
There were 402 patients with a median age of 66 years (range 23–92) of whom 226 (56%) were male. The EFV was larger in patients with CP (112 ± 55 cm3 vs. 89 ± 39 cm3), PCP (110 ± 57 cm3 vs. 98 ± 45 cm3) and NCP (115 ± 44 cm3 vs. EFV 100 ± 52 cm3. In the 192 patients with PCP or NCP, on multivariable analysis, after adjusting for conventional cardiovascular risk factors, EFV was an independent predictor of ≥70% coronary artery stenosis (OR 3.0, 95% CI 1.3–6.6, p=0.008), any high risk plaque features (OR 1.7, 95% CI 0.9–3.4, p=0.04) and low attention plaque (OR 2.4, 95% CI 1.1–5.1, p=0.02), but not of positive remodeling.
Epicardial fat volume is larger in patients with CP, PCP and NCP. In patients with NCP and PCP, EFV is significantly associated with severe coronary stenosis, high risk plaque features and low attenuation plaque.
Epicardial fat volume; coronary computed tomography angiography; coronary artery stenosis; high-risk plaque features
Perivascular fat through the secretion of paracrine and pro-inflammatory mediators may play a role in obesity-mediated vascular disease. We sought to examine associations between adipose tissue depots immediately surrounding the thoracic aorta, metabolic risk factors, and vascular calcification.
In participants free of cardiovascular disease (CVD) from the Framingham Heart Study Offspring cohort who underwent computed tomography (n=1067, mean age 59 years, 56.1% women), thoracic peri-aortic fat depots were quantified. Visceral abdominal tissue (VAT) and calcification of the thoracic and abdominal aorta were also measured.
Peri-aortic fat depots were correlated with body mass index, waist circumference (WC), VAT (all p<0.0001), hypertension (p<0.007), lower HDL (p<0.0001), serum triglycerides (p<0.0001), impaired fasting glucose (p<0.005), and diabetes (p=0.02). These associations generally remained significant after adjustment for BMI and WC (all p-values<0.05), but not after VAT adjustment. Thoracic aortic fat was associated with thoracic calcification in models containing VAT (OR 1.31, 95% CI 1.01–1.71, p=0.04), but was not significant after adjustment for CVD risk factors (OR 1.16, 95% CI 0.88–1.51, p=0.30). Thoracic aortic fat, however, was associated with abdominal aortic calcification (OR 1.48, 95% CI 1.11–1.98, p=0.008) and coronary artery calcification (OR 1.47, 95% CI 1.09–1.98, p=0.001) even in models including CVD risk factors and VAT.
Thoracic peri-aortic fat is associated with measures of adiposity, metabolic risk factors, and coronary and abdominal aortic calcification.
Obesity; atherosclerosis; calcium; risk factors
Epicardial fat, the local visceral fat depot enclosed by the visceral pericardial sac, surrounds the coronary arteries for most of their course, and may contribute to the development of coronary atherosclerosis through local production of inflammatory cytokines. Several studies which measured epicardial fat volume noninvasively have shown a relationship of increased epicardial fat volume with coronary artery disease, with the presence and progression of coronary plaque, major adverse cardiovascular events, myocardial ischemia and atrial fibrillation. Quantitative measurement of epicardial fat volume from noninvasive imaging modalities such as CT and MRI are feasible, and may play a clinical role in cardiovascular risk assessment. The evidence to date warrants larger studies with follow-up to further investigate the role of epicardial fat as an imaging marker with prognostic importance.
Epicardial and thoracic fat; noninvasive measurement; coronary artery disease; clinical implications
A low-grade state of adipose tissue inflammation associated with obesity has been linked to mechanisms of systemic metabolic dysfunction. However, the relation of clinical phenotypes to depot-specific inflammation has not been well examined in human obesity.
To characterize the inflammatory status of subcutaneous and visceral fat depots, as assessed by tissue presence of macrophage crown-like structures (CLS) as a hallmark of chronic inflammation, and determine the relation of systemic insulin resistance to inflammatory abnormalities in subcutaneous and visceral fat.
We collected adipose tissue simultaneously from subcutaneous and visceral (omental and mesenteric) depots in 92 obese participants (age 42±11 years; BMI⩾30 kg m−2) during planned bariatric surgery. Using immunohistochemistry, we categorized individuals as CLS+ or CLS− based on the presence or absence, respectively, of macrophage CLS in subcutaneous (CLSs), omental (CLSo) and mesenteric (CLSm) adipose depots.
The majority of participants exhibited adipose tissue inflammation manifest by the presence of CLS (CLS+) in both subcutaneous and intra-abdominal visceral depots. CLS status in subcutaneous fat was highly sensitive and modestly specific for inflammation of visceral fat. In multivariable models, plasma insulin and homeostatis model assessment levels were positively associated with CLS+ status in all depots independent of age, waist circumference, BMI and type 2 diabetes, and worsened with the increasing number of adipose regions involved.
In severely obese participants, systemic insulin resistance is linked to adipose inflammation in both subcutaneous and visceral depots. The findings suggest that examination of subcutaneous regions that are more easily accessible by transcutaneous biopsy may prove useful in clinical studies designed to investigate adipose phenotypes in relation to human disease.
inflammation; obesity; insulin resistance
The white adipose organ is composed of both subcutaneous and several intra-abdominal depots. Excess abdominal adiposity is a major risk factor for metabolic disease in rodents and humans, while expansion of subcutaneous fat does not carry the same risks. Brown adipose produces heat as a defense against hypothermia and obesity, and the appearance of brown-like adipocytes within white adipose tissue depots is associated with improved metabolic phenotypes. Thus, understanding the differences in cell biology and function of these different adipose cell types and depots may be critical to the development of new therapies for metabolic disease. Here, we found that Prdm16, a brown adipose determination factor, is selectively expressed in subcutaneous white adipocytes relative to other white fat depots in mice. Transgenic expression of Prdm16 in fat tissue robustly induced the development of brown-like adipocytes in subcutaneous, but not epididymal, adipose depots. Prdm16 transgenic mice displayed increased energy expenditure, limited weight gain, and improved glucose tolerance in response to a high-fat diet. shRNA-mediated depletion of Prdm16 in isolated subcutaneous adipocytes caused a sharp decrease in the expression of thermogenic genes and a reduction in uncoupled cellular respiration. Finally, Prdm16 haploinsufficiency reduced the brown fat phenotype in white adipose tissue stimulated by β-adrenergic agonists. These results demonstrate that Prdm16 is a cell-autonomous determinant of a brown fat–like gene program and thermogenesis in subcutaneous adipose tissues.
This study aimed to test the association of individual adipose depots on cardiometabolic outcomes; whether the association varied by depot; and if the associations differed by race/ethnicity or sex in early pubertal children.
320 children (53% male) aged 7–12y self-identified as African- (AA; n=114), European- (EA; n=120), or Hispanic American (HA; n=86) participated. Insulin dynamics were assessed by intravenous glucose tolerance test; body composition with DXA; fat distribution with CT.
AA had the least fat in each depot and HA had the most. Fat accumulation negatively impacted cardiometabolic outcomes independent of race/ethnicity or sex. AA and females were reproductively more mature. In AA and HA each measure of adiposity influenced the insulin sensitivity index (SI), whereas intra-abdominal adipose tissue (IAAT) did not contribute to SI in EA. IAAT was positively associated with blood pressure in AA, only. In females, adiposity adversely influenced cardiometabolic outcomes, such that total fat mass, IAAT, and/or SAAT was inversely associated with SI, and positively associated with blood pressure and fasting insulin.
IAAT is uniquely related to metabolic risk factors in Hispanic Americans, African Americans, and girls, suggesting that either the threshold for adverse effects of IAAT is lower, or that IAAT metabolism differs in these groups.
Intra-abdominal adipose tissue; puberty; race/ethnicity; sex differences; pediatric obesity
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.
Obesity; Lipoproteins; Inflammation; Atherosclerosis; Diabetes
White adipose tissue (WAT) is a multi-faceted endocrine organ involved in energy storage, metabolism, immune function and disease pathogenesis. In contrast to subcutaneous fat, visceral fat (V-WAT) has been associated with numerous diseases and metabolic disorders, indicating specific functions related to anatomical location. Although visceral depots are often used interchangeably in V-WAT-associated disease studies, there has been a recent subdivision of V-WAT into “true visceral” and non-visceral intra-abdominal compartments. These were associated with distinct physiological roles, illustrating a need for depot-specific information. Here, we use FACS analysis to comparatively characterize the leukocyte and progenitor populations in the stromal vascular fraction (SVF) of peritoneal serous fluid (PSF), parametrial (pmWAT), retroperitoneal (rpWAT), and omental (omWAT) adipose tissue from seven-month old C57BL/6 female mice. We found significant differences in SVF composition between all four microenvironments. PSF SVF was comprised almost entirely of CD45+ leukocytes (>99%), while omWAT contained less, but still almost two-fold more leukocytes than pmWAT and rpWAT (75%, 38% and 38% respectively; p<0.01). PmWAT was composed primarily of macrophages, whereas rpWAT more closely resembled omWAT, denoted by high levels of B1 B-cell and monocyte populations. Further, omWAT harbored significantly higher proportions of T-cells than the other tissues, consistent with its role as a secondary lymphoid organ. These SVF changes were also reflected in the gene expression profiles of the respective tissues. Thus, intra-abdominal fat pads represent independent immunomodulatory microenvironments and should be evaluated as distinct entities with unique contributions to physiological and pathological processes.
Visceral adipose tissue (VAT) and hepatic fat are associated with insulin resistance and vary by sex and ethnicity. Recently, pancreatic fat fraction (PFF) has also been linked with increasing obesity. Our aim was to assess ethnic and sex differences in PFF and its relationship to other fat depots, circulating free fatty acids (FFA), insulin secretion and sensitivity, and inflammation in obese adolescents and young adults.
RESEARCH DESIGN AND METHODS
We examined 138 (40 males, 98 females) obese Hispanics and African Americans (13–25 years). Subcutaneous adipose tissue and VAT volumes, hepatic fat fraction (HFF), and PFF were determined by magnetic resonance imaging. Insulin sensitivity and β-cell function were assessed during an intravenous glucose tolerance test.
Hispanics had higher PFF than African Americans (7.3 ± 3.8 vs. 6.2 ± 2.6%, P = 0.03); this ethnic difference was higher in young adults compared with children and adolescents (ethnicity × age: P = 0.01). Males had higher PFF than females (P < 0.0001). PFF was positively correlated with VAT (r = 0.45, P < 0.0001), HFF (r = 0.29, P < 0.0001), and FFA (r = 0.32, P = 0.001). PFF positively correlated with inflammatory markers but lost significance when adjusted for VAT. In multiple stepwise regression analysis, VAT and FFA were the best predictors of PFF (adjusted R2 = 0.40). There were no significant correlations between PFF and markers of insulin sensitivity or β-cell function.
PFF is higher in Hispanics than African Americans, and this difference increases with age. In young obese individuals, PFF is related to VAT, HFF, and circulating FFA, thus possibly contributing to their increased risk for type 2 diabetes and related metabolic disorders.
Aortic valve calcification (AVC) is associated with cardiovascular risk factors and coronary artery calcification. We sought to determine whether AVC is associated with the presence and extent of overall plaque burden, as well as to plaque composition (calcified, mixed, and non-calcified).
We examined 357 subjects (mean age: 53 ± 12 years, 61% male) who underwent contrast-enhanced ECG-gated 64-slice multi-detector computed tomography from the ROMICAT trial for the assessment of presence and extent of coronary plaque burden according to the 17-coronary segment model and presence of AVC.
Patients with AVC (n=37, 10%) were more likely than those without AVC (n=320, 90%) to have coexisting presence of any coronary plaque (89% vs. 46%, p<0.001) and had a greater extent of coronary plaque burden (6.4 segments vs. 1.8 segments, p<0.001). Those with AVC had over 3-fold increase odds of having any plaque (adjusted odds ratio [OR] 3.6, p=0.047) and an increase of 2.5 segments of plaque (p<0.001) as compared to those without AVC. When stratified by plaque composition, AVC was associated most with calcified plaque (OR 5.2, p=0.004), then mixed plaque (OR 3.2, p=0.02), but not with non-calcified plaque (p=0.96).
AVC is associated with the presence and greater extent of coronary artery plaque burden and may be part of the later stages of the atherosclerosis process, as its relation is strongest with calcified plaque, less with mixed plaque, and nonsignificant with non-calcified plaque. If AVC is present, consideration for aggressive medical therapy may be warranted.
Aortic valve calcification; coronary artery disease; multi-detector computed tomography; calcified plaque; non-calcified plaque; mixed plaque
Mainly dependent on hormone-sensitive lipase, lipolysis is differently impaired between fat depots in human obesity. Perilipin A expression is a critical element in adipocyte lipolysis. The present study aimed at comparing expression and subcellular distribution of perilipin and hormone-sensitive lipase in two abdominal adipose tissues of lean and obese women. We examined whether regional differences in perilipin expression contribute to impaired lipolytic rates.
Abdominal subcutaneous and omental adipose tissues were obtained from six lean and ten obese women. We measured total protein content and relative distribution of hormone-sensitive lipase and perilipin proteins between lipid and non-lipid fractions in tissue homogenates. Hormone-sensitive lipase and perilipin mRNA levels, adipocyte size, basal (non-stimulated) and noradrenaline-stimulated lipolysis in isolated adipocytes were determined.
Adipocytes were significantly larger in the obese versus the lean women and in subcutaneous versus omental fat. Expressed as a function of cell number, basal lipolysis and noradrenaline responsiveness were higher in subcutaneous versus omental adipocytes from the obese women (P < 0.05). Despite higher or identical mRNA levels in the lean and the obese subjects and in subcutaneous and omental tissues, perilipin protein expression was lower in both depots in the obese versus the lean women, and in subcutaneous versus omental in both lean and obese women (P < 0.05). Perilipin was mostly (above 80%) present in the lipid fraction in both depots from the obese patients and the value decreased to 60% in the lean subjects (P < 0.05). Perilipin protein expression was inversely correlated to adipocyte size and basal lipolysis in both depots. Despite higher mRNA levels, hormone-sensitive lipase protein expression decreased in both depots of the obese women. Regional difference for hormone-sensitive lipase was reported in lipid fraction of subcutaneous fat of the obese subjects: hormone-sensitive lipase content was twice as low as in omental adipose tissue.
In both fat depots, a reduced perilipin protein expression was observed in women obesity. Perilipin protein level may contribute to differences in basal lipolysis and in adipocyte size between fat depots and may regulate lipid accumulation in adipocytes. Differences in hormone-sensitive lipase subcellular distribution were reported between fat depots in the obese women.