Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

The complex relationship between metabolic disease risk and body fat distribution in humans involves cellular characteristics which are specific to body fat compartments. Here we show depotspecific differences in the stromal vascual fraction of visceral and subcutaneous adipose tissue by performing single-cell RNA sequencing of tissue specimen from obese individuals. We characterize multiple immune cells, endothelial cells, fibroblasts, adipose and hematopoietic stem cell progenitors. Subpopulations of adipose-resident immune cells are metabolically active and associated with metabolic disease status and those include a population of potential dysfunctional CD8+ T cells expressing metallothioneins. We identify multiple types of adipocyte progenitors that are common across depots, including a subtype enriched in individuals with type 2 diabetes. Depot-specific analysis reveals a class of adipocyte progenitors unique to visceral adipose tissue, *

Adipose tissue located within the abdominal cavity has been suggested to be functionally and metabolically distinct from that of the subcutaneous compartment. These differences could play a role in obesity‐related complications. The aim of this study was to compare gene expression profiles of subcutaneous and visceral adipose tissues of 10 nondiabetic, normolipidemic obese men. Affymetrix human U133A arrays (10 arrays for subcutaneous fat samples and 10 arrays for visceral fat samples) were used. Differential gene expression was confirmed by real‐time polymerase chain reaction in a subset of genes. A total of 5894 transcripts were detected in both depots in all 10 subjects, and 409 transcripts representing 347 encoded genes were differentially expressed. Of these, 131 genes were expressed at higher levels in subcutaneous adipose tissue, and 216 were expressed more abundantly in visceral fat. Differentially expressed profiles included genes of the Wnt signaling pathway, as well as CEPBA and HOX genes. In addition, genes involved in lipolytic stimuli and cytokine secretion were differentially expressed. The identification of a consistent and rather uniform pattern of differentially expressed genes between the two fat depots using multiple array replicates (10 arrays per fat compartment) generated new perspectives for future research on regional differences in adipose tissue biology.

In contrast, in case/control and family-based study populations from Scandinavia, we saw no effect on BMI with either of these promoter variants. No association was seen with diabetes in any of the population samples.

. Abdominal visceral fat is associated with a BclI restriction fragment length polymorphism at the glucocorticoid receptor gene locus. Obes Res. 1997;5: 186-192. Several investigations have suggested that body fat distribution is influenced by nonpathologic variations in the responsiveness to cortisol. Genetic variations in the glucocorticoid receptor (GRL) could therefore potentially have an impact on the level of abdominal fat. A restriction fragment length polymorphism (RFLP) has previously been detected with the BcZI restriction enzyme in the GRL gene identifying two alleles with fragment lengths of 4.5 and 2.3 kb. This study investigates whether abdominal fat areas measured by computerized tomography (CT) are associated with this polymorphism in 152 middle-aged men and women. The less frequent 4.5-kb allele was found to be associated with a higher abdominal visceral fat (AVF) area independently of total body fat mass (4.514.5 vs. 2.312.3 kb genotype; men: 190.7 f 30.1 vs. 150.7 2 33.3 cm', p=0.04; women: 132.7 f 37.3 vs. 101.3 34.5 cm' , p=0.06). However, the association with AVF was seen only in subjects of the lower tertile of the percent body fat level. In these subjects, the polymorphism was found to account for 41% @=0.003) and 35% @=0.007), in men and women, respectively, of the total variance in AVF area. The consistent association between the GRL polymorphism detected with BcZI and AVF area suggests that this gene or a locus in linkage disequilibrium with the BcZI restriction site may contribute to the accumulation of AVF.

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The results suggest that NMB is a very strong candidate gene of eating behaviors and predisposition to obesity.