Kalypso Karastergiou

Sex differences in human adipose tissues – the biology of pear shape

Women have more body fat than men, but in contrast to the deleterious metabolic consequences of the central obesity typical of men, the pear-shaped body fat distribution of many women is associated with lower cardiometabolic risk. To understand the mechanisms regulating adiposity and adipose tissue distribution in men and women, significant research attention has focused on comparing adipocyte morphological and metabolic properties, as well as the capacity of preadipocytes derived from different depots for proliferation and differentiation. Available evidence points to possible intrinsic, cell autonomous differences in preadipocytes and adipocytes, as well as modulatory roles for sex steroids, the microenvironment within each adipose tissue, and developmental factors. Gluteal-femoral adipose tissues of women may simply provide a safe lipid reservoir for excess energy, or they may directly regulate systemic metabolism via release of metabolic products or adipokines. We provide a brief overview of the relationship of fat distribution to metabolic health in men and women, and then focus on mechanisms underlying sex differences in adipose tissue biology.

Deconstructing the roles of glucocorticoids in adipose tissue biology and the development of central obesity

Central obesity is associated with insulin resistance and dyslipidemia. Thus, the mechanisms that control fat distribution and its impact on systemic metabolism have importance for understanding the risk for diabetes and cardiovascular disease. Hypercortisolemia at the systemic (Cushings syndrome) or local levels (due to adipose-specific overproduction via 11β-hydroxysteroid dehydrogenase 1) results in the preferential expansion of central, especially visceral fat depots. At the same time, peripheral subcutaneous depots can become depleted. The biochemical and molecular mechanisms underlying the depot-specific actions of glucocorticoids (GCs) on adipose tissue function remain poorly understood. GCs exert pleiotropic effects on adipocyte metabolic, endocrine and immune functions, and dampen adipose tissue inflammation. GCs also regulate multiple steps in the process of adipogenesis. Acting synergistically with insulin, GCs increase the expression of numerous genes involved in fat deposition. Variable effects of GC on lipolysis are reported, and GC can improve or impair insulin action depending on the experimental conditions. Thus, the net effect of GC on fat storage appears to depend on the physiologic context. The preferential effects of GC on visceral adipose tissue have been linked to higher cortisol production and glucocorticoid receptor expression, but the molecular details of the depot-dependent actions of GCs are only beginning to be understood. In addition, increasing evidence underlines the importance of circadian variations in GCs in relationship to the timing of meals for determining their anabolic actions on the adipocyte. In summary, although the molecular mechanisms remain to be fully elucidated, there is increasing evidence that GCs have multiple, depot-dependent effects on adipocyte gene expression and metabolism that promote central fat deposition. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

Distinct Developmental Signatures of Human Abdominal and Gluteal Subcutaneous Adipose Tissue Depots

CONTEXT Fat distribution differs in men and women, but in both sexes, a predominantly gluteal-femoral compared with abdominal (central) fat distribution is associated with lower metabolic risk. Differences in cellular characteristics and metabolic functions of these depots have been described, but the molecular mechanisms involved are not understood. OBJECTIVE Our objective was to identify depot- and sex-dependent differences in gene expression in human abdominal and gluteal sc adipose tissues. DESIGN AND METHODS Abdominal and gluteal adipose tissue aspirates were obtained from 14 premenopausal women [age 27.5 ± 7.0 yr, body mass index (BMI) 27.3 ± 6.2 kg/m(2), and waist-to-hip ratio 0.82 ± 0.04] and 21 men (age 29.7±7.4 yr, BMI 27.2 ± 4.5 kg/m(2), and waist-to-hip ratio 0.91 ± 0.07) and transcriptomes were analyzed using Illumina microarrays. Expression of selected genes was determined in isolated adipocytes and stromal vascular fractions from each depot, and in in vitro cultures before and after adipogenic differentiation. RESULTS A total of 284 genes were differentially expressed between the abdominal and gluteal depot, either specifically in males (n = 66) or females (n = 159) or in both sexes (n = 59). Most notably, gene ontology and pathway analysis identified homeobox genes (HOXA2, HOXA3, HOXA4, HOXA5, HOXA9, HOXB7, HOXB8, HOXC8, and IRX2) that were down-regulated in the gluteal depot in both sexes (P = 2 × 10(-10)). Conversely, HOXA10 was up-regulated in gluteal tissue and HOXC13 was detected exclusively in this depot. These differences were independent of BMI, were present in both adipocytes and stromal vascular fractions of adipose tissue, and were retained throughout in vitro differentiation. CONCLUSIONS We conclude that developmentally programmed differences may contribute to the distinct phenotypic characteristics of peripheral fat.

Shaping fat distribution: New insights into the molecular determinants of depot‐ and sex‐dependent adipose biology

To review recent advances in understanding the cellular mechanisms that regulate fat distribution.

Identification of a novel lncRNA in gluteal adipose tissue and evidence for its positive effect on preadipocyte differentiation

Peripheral lower body fat is associated with lower cardiometabolic risk. Physiological differences in gluteal compared with abdominal subcutaneous (sc) adipocyte functions are known but the molecular basis for depot differences in adipocyte function is poorly understood. Our goal is to identify novel gene regulatory pathways that underlie the heterogeneity of human fat distribution.

Multiple Adipose Depots Increase Cardiovascular Risk via Local and Systemic Effects

Adipose tissue modifies the development of cardiovascular disease in a complex manner: obesity is a major risk factor, especially when accompanied by a central fat distribution. For that reason the characteristics of visceral adipose tissue have attracted most of the research interest thus far, and measurement of waist circumference is now recommended for everyday clinical practice. However, the direct, causative role of visceral fat in cardiometabolic disease remains to be established. Epidemiological and clinical studies show that accumulation of fat subcutaneously, in the gluteofemoral area, is protective against cardiovascular disease, but the exact molecular mechanisms remain unclear. In the last few years, imaging has allowed the study of smaller fat depots that may interact locally with important tissues: epicardial fat with the myocardium, perivascular fat with the vessel wall and the developing atherosclerotic plaque, and renal sinus fat with the renal artery. Unraveling the heterogeneous fat distribution and metabolic phenotypes in human obesity will facilitate optimal assessment of cardiovascular risk in overweight and obese individuals.

The Interplay Between Sex, Ethnicity, and Adipose Tissue Characteristics

The obesity epidemic in the USA affects disproportionately women and the ethnic minorities. On the other hand, female sex is traditionally associated with a favorable fat distribution preferentially in the subcutaneous depots of the lower body and with improved endocrine and metabolic function of the adipose tissue. However, these data are derived from predominantly non-Hispanic white populations. This review discusses fat distribution patterns in women of diverse ethnic backgrounds, together with data on the release of adipokines from adipose tissue in these populations. Very little information is available on how the metabolic function of the adipocyte differs depending on ethnicity. Thus, it becomes clear that future clinical and translational research should explicitly discuss and take into account the sex and ethnic background of the populations studied.

Depot Dependent Effects of Dexamethasone on Gene Expression in Human Omental and Abdominal Subcutaneous Adipose Tissues from Obese Women

Glucocorticoids promote fat accumulation in visceral compared to subcutaneous depots, but the molecular mechanisms involved remain poorly understood. To identify long-term changes in gene expression that are differentially sensitive or responsive to glucocorticoids in these depots, paired samples of human omental (Om) and abdominal subcutaneous (Abdsc) adipose tissues obtained from obese women during elective surgery were cultured with the glucocorticoid receptor agonist dexamethasone (Dex, 0, 1, 10, 25 and 1000 nM) for 7 days. Dex regulated 32% of the 19,741 genes on the array, while 53% differed by Depot and 2.5% exhibited a Depot*Dex concentration interaction. Gene set enrichment analysis showed Dex regulation of the expected metabolic and inflammatory pathways in both depots. Cluster analysis of the 460 transcripts that exhibited an interaction of Depot and Dex concentration revealed sets of mRNAs for which the responses to Dex differed in magnitude, sensitivity or direction between the two depots as well as mRNAs that responded to Dex only in one depot. These transcripts were also clearly depot different in fresh adipose tissue and are implicated in processes that could affect adipose tissue distribution or functions (e.g. adipogenesis, triacylglycerol synthesis and storage, insulin action). Elucidation of the mechanisms underlying the depot differences in the effect of Dex on the expression of specific genes and pathways that regulate adipose function may offer novel insights into understanding the biology of visceral adipose tissues and their links to metabolic health.

MicroRNA-196 Regulates HOX Gene Expression in Human Gluteal Adipose Tissue

Lower body fat is associated with diminishing cardiometabolic risk. Physiological differences between gluteofemoral and abdominal subcutaneous adipocyte functions are known, but the molecular basis for depot differences in adipocyte function is poorly understood. The objective of this study was to identify depot differences in microRNA (miRNA) expression in human abdominal and gluteofemoral subcutaneous adipose tissues and their implication in gene regulation.

Growth hormone receptor expression in human gluteal versus abdominal subcutaneous adipose tissue: Association with body shape

Growth hormone (GH) administration reduces abdominal, but not lower body, fat mass. To gain insight into the underlying mechanisms, this study examined the expression of the GH receptor (GHR) and some of its targets in abdominal and gluteal adipose tissue.