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Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
PURPOSE - To test the hypothesis that a whole-body fat-water MRI (FWMRI) protocol acquired at 3 Tesla combined with semi-automated image analysis techniques enables precise volume and mass quantification of adipose, lean, and bone tissue depots that agree with static scale mass and scale mass changes in the context of a longitudinal study of large-breed dogs placed on an obesogenic high-fat, high-fructose diet.
MATERIALS AND METHODS - Six healthy adult male dogs were scanned twice, at weeks 0 (baseline) and 4, of the dietary regiment. FWMRI-derived volumes of adipose tissue (total, visceral, and subcutaneous), lean tissue, and cortical bone were quantified using a semi-automated approach. Volumes were converted to masses using published tissue densities.
RESULTS - FWMRI-derived total mass corresponds with scale mass with a concordance correlation coefficient of 0.931 (95% confidence interval = [0.813, 0.975]), and slope and intercept values of 1.12 and -2.23 kg, respectively. Visceral, subcutaneous and total adipose tissue masses increased significantly from weeks 0 to 4, while neither cortical bone nor lean tissue masses changed significantly. This is evidenced by a mean percent change of 70.2% for visceral, 67.0% for subcutaneous, and 67.1% for total adipose tissue.
CONCLUSION - FWMRI can precisely quantify and map body composition with respect to adipose, lean, and bone tissue depots. The described approach provides a valuable tool to examine the role of distinct tissue depots in an established animal model of human metabolic disease.
Copyright © 2013 Wiley Periodicals, Inc.
Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. We hypothesized that genetic loci would be associated with pericardial fat independent of other body fat depots. Pericardial fat was quantified in 5,487 individuals of European ancestry from the Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of pericardial fat adjusted for age, sex, weight, and height. A weighted z-score meta-analysis was conducted, and validation was obtained in an additional 3,602 multi-ethnic individuals from the MESA study. We identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7 × 10(-08)). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38), although we observed direction-consistent, nominal significance with visceral fat adjusted for BMI (p = 0.01) in the Framingham Heart Study. Our findings were robust among African ancestry (n = 1,442, p = 0.001), Hispanic (n = 1,399, p = 0.004), and Chinese (n = 761, p = 0.007) participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.
BACKGROUND - Visceral adiposity is associated with metabolic risk. Given that angiogenesis is a key feature of adipogenesis, variation in the association of levels of circulating vascular growth factors (and their soluble receptors) with distinct body fat compartments may explain differences in the systemic pathogenicity of regional fat depots.
METHODS AND RESULTS - Four body fat compartments [visceral adipose tissue (VAT), sc adipose tissue (SAT), thoracic periaortic fat, and pericardial fat] derived from computed tomography were related to serum concentrations of vascular endothelial growth factor (VEGF), the soluble VEGF receptor (fms-like tyrosine kinase-1), hepatocyte growth factor (HGF), and angiopoietin-2 and its soluble receptor (soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 2 sTie-2) in 1806 Framingham Heart Study participants (mean age 44.9 yr, 44.5% women). In multivariable models, we observed positive associations between several fat compartments and VEGF and HGF levels. The magnitude of the associations were similar for VAT, SAT, and periaortic fat. We observed effect modification by sex. A stronger association was observed between VAT and HGF levels in women; higher VAT and periaortic fat were jointly associated with higher HGF concentrations (P=0.02 and P=0.051, respectively). In women within the highest tertile of VAT, HGF levels significantly increased with higher periaortic fat (P=0.0005).
CONCLUSIONS - In our large community-based sample, greater adiposity was associated with higher circulating growth factor levels in general. Additional studies are warranted to confirm the stronger association of VAT and periaortic fat with HGF in women and to examine its potential contribution to the sex-related differences in cardiometabolic risk.
AIMS/HYPOTHESIS - Intramyocellular lipids (IMCL) accumulation is a classical feature of metabolic diseases. We hypothesised that IMCL accumulate mainly as a consequence of increased adiposity and independently of type 2 diabetes. To test this, we examined IMCL accumulation in two different models and four different populations of participants: muscle biopsies and primary human muscle cells derived from non-obese and obese participants with or without type 2 diabetes. The mechanism regulating IMCL accumulation was also studied.
METHODS - Muscle biopsies were obtained from ten non-obese and seven obese participants without type 2 diabetes, and from eight non-obese and eight obese type 2 diabetic patients. Mitochondrial respiration, citrate synthase activity and both AMP-activated protein kinase and acetyl-CoA carboxylase phosphorylation were measured in muscle tissue. Lipid accumulation in muscle and primary myotubes was estimated by Oil Red O staining and fatty acid translocase (FAT)/CD36 localisation by immunofluorescence.
RESULTS - Obesity and type 2 diabetes are independently characterised by skeletal muscle IMCL accumulation and permanent FAT/CD36 relocation. Mitochondrial function is not reduced in type 2 diabetes. IMCL accumulation was independent of type 2 diabetes in cultured myotubes and was correlated with obesity markers of the donor. In obese participants, membrane relocation of FAT/CD36 is a determinant of IMCL accumulation.
CONCLUSIONS/INTERPRETATION - In skeletal muscle, mitochondrial function is normal in type 2 diabetes, while IMCL accumulation is dependent upon obesity or type 2 diabetes and is related to sarcolemmal FAT/CD36 relocation. In cultured myotubes, IMCL content and FAT/CD36 relocation are independent of type 2 diabetes, suggesting that distinct factors in obesity and type 2 diabetes contribute to permanent FAT/CD36 relocation ex vivo.
A multi-institutional collaboration was forged to implement a study of the relationship between Vitamin D and breast density among medically underserved women. This effort resulted in techniques to measure vitamin D levels, breast density, and sunlight exposure. Outcomes from this collaboration may provide insight to researchers conducting similar investigations.
OBJECTIVE - To examine whether childbearing is associated with increased visceral adiposity and whether the increase is proportionally larger than other depots.
METHODS AND PROCEDURES - This prospective study examined changes in adiposity assessed via computed tomography (CT) and dual-energy X-ray absorptiometry among 122 premenopausal women (50 black, 72 white) examined in 1995-1996 and again in 2000-2001. During the 5-year interval, 14 women had one interim birth and 108 had no interim births. Multiple linear regression models estimated mean (95% confidence interval (CI)) 5-year changes in anthropometric and adiposity measures by interim births adjusted for age, race, and changes in total and subcutaneous adiposity.
RESULTS - We found no significant differences between one interim birth and no interim births for 5-year changes in weight, BMI, total body fat, subcutaneous adipose tissue, or total abdominal adipose tissue. Visceral adipose tissue increased by 40 and 14% above initial levels for 1 birth and 0 birth groups, respectively. Having 1 birth vs. 0 births was associated with a greater increase in visceral adipose tissue of 18.0 cm2 (4.8, 31.2), P<0.01; gain of 27.1 cm2 (14.5, 39.7) vs. 9.2 cm2 (4.8, 13.6), and a borderline greater increase in waist girth of 2.3 cm (0, 4.5), P=0.05; gain of 6.3 cm (4.1, 8.5) vs. 4.0 cm (3.2, 4.8), controlling for gain in total body fat and covariates.
DISCUSSION - Pregnancy may be associated with preferential accumulation of adipose tissue in the visceral compartment for similar gains in total body fat. Further investigation is needed to confirm these findings and determine whether excess visceral fat deposition with pregnancy adversely affects metabolic risk profiles among women.
BACKGROUND - Leptin is strongly associated with adiposity and few studies have investigated its role in Mexican-Americans. The aims of this study were to examine the association of serum leptin concentration with adiposity and body fat distribution in Mexican-Americans and to develop a predictive model of serum leptin concentration for this ethnic group.
METHODS - Three hundred fifty-two college students (242 women, 110 men; age 18-30 years) were evaluated in this cross-sectional study. Body fat content was assessed using bioelectrical impedance analysis. Correlation between serum leptin levels and several markers of adiposity and body fat distribution were examined in both men and women. Multiple regression analysis was performed to create the predictive model.
RESULTS - Women had higher serum leptin concentrations than men for the same levels of adiposity. After controlling for gender and body fat, only fat mass (FM) expressed in kg, was significantly correlated with serum leptin concentration in men (partial rho = 0.811, p <0.001), whereas body mass index (BMI), hip circumference (HC), and FM expressed in kg, were significantly correlated with serum leptin concentration in women (partial rho = 0.214, p <0.001; partial rho = 0.201, p <0.01; and partial rho = 0.818, p <0.001, respectively). Percent body fat (PBF) was the only significant predictor of serum leptin concentration among men, explaining 42% of the variance in serum leptin concentration. In addition to PBF, waist circumference (WC) and HC were significant predictors of serum leptin concentration among women explaining 65% of the variance in serum leptin concentration.
CONCLUSIONS - Serum leptin concentration is a function of adiposity as determined by PBF in both Mexican-American men and women. HC and WC are associated with serum leptin concentration in Mexican-American women but not in men. BMI alone should not be used in evaluating the association of serum leptin concentration with body fatness in Mexican-Americans.
Intraabdominal fat (IAF) area is often measured indirectly in epidemiologic studies. The authors recruited 147 participants from the second examination (1990-1992) of the Atherosclerosis Risk in Communities Study to examine IAF area and determine whether there were differences in IAF area and distribution by location. Magnetic resonance imaging was used to image four 10-mm slices between the second and fourth lumbar vertebrae by an inverse recovery method, and IAF was calculated from each image. The authors constructed gender-specific mixed models with IAF area as the outcome and the location of imaging along the torso as the independent variable, using random intercepts to account for between-person variation in IAF area. The torso location of IAF measurement was a significant predictor of IAF area in both men (p = 0.02) and women (p < 0.0001) after adjustment for body mass index. A significant positive interaction between age and location was seen in men, with increasing IAF area moving down the torso with older ages. Using magnetic resonance imaging, location along the torso yields different IAF areas and distributions independently of body mass index in both genders, with measurement at the second lumbar vertebra (slightly above the umbilicus) capturing the largest amount of IAF. Studies that attempt to link IAF with cardiovascular disease risk factors should consider measurement location to accurately capture the association.