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.

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 risk for diabetes and cardiovascular disease. Hypercortisolemia at the systemic (Cushing’s 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 function, 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.

We conclude that developmentally programmed differences may contribute to the distinct phenotypic characteristics of peripheral fat.

Please cite this article as: Karastergiou, K., Mohamed-Ali, V., The autocrine and paracrine roles of adipokines, Molecular and Cellular Endocrinology (2008), doi:10.1016/j.mce.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 35A c c e p t e d M a n u s c r i p t Abstract.Obesity, defined by an excess of adipose tissue, is often associated with the development of various metabolic diseases. The increased and inappropriate deposition of this tissue contributes to hyperglycemia, hyperlipidemia, insulin resistance, endothelial dysfunction and chronic inflammation. Recent evidence suggests that factors expressed and secreted by the adipose tissue, adipokines, may contribute to the development of these abnormalities by mechanisms including inhibition of adipogenesis, adipocyte hypertrophy and death, immune cell infiltration and disruption of tissue metabolism. The presence of adipokine receptors in adipocytes renders these cells available to autocrine and paracrine effects of adipokines. In this review the reported local effects of adipokines on adipose tissue structure, inflammation and regulation of metabolic functions, in the face of over-nutrition and consequent obesity, are outlined. Elucidating the local regulation of white adipocyte development and function could help in the design of effective, tissue-specific therapies for obesity-associated diseases.

Objective-To investigate the hypothesis that release of adipokines by epicardial adipose tissue (EAT) is dysregulated in obesity and/or coronary artery disease (CAD), along with the previously documented expansion of the tissue, and that these molecules induce pathophysiological changes in human monocytes and coronary artery endothelial cells. Methods and Results-In white nondiabetic patients with CAD (nϭ62) or without CAD (control group) (nϭ32), subdivided by body mass index of Յ27 and Ͼ27, 13 cytokines were identified by protein array analysis as EAT products. Interleukin 6, interleukin 8, monocyte chemoattractant protein 1, plasminogen activator inhibitor 1, growth-related oncogene-␣, and macrophage migration inhibitory factor were the most abundant. Adiponectin release was suppressed in patients with obesity and CAD, and regulated on activation T-cell and secreted (RANTES) was induced in patients with CAD. EAT-conditioned media induced migration of monocytic tryptophan hydroxylase 1 (THP-1) cells, an effect exacerbated in those with CAD. Moreover, conditioned media from patients with CAD and body mass index of Ͼ27 increased the adhesion of THP-1 cells to human coronary artery endothelial cells by 15.1% (Pϭ0.002) and expression of intercellular adhesion molecule 1 by 2.8-fold (Pϭ0.002). This effect was reversed by recombinant adiponectin. Conclusion-EAT

Objective To review recent advances in understanding the cellular mechanisms that regulate fat distribution. Methods We highlight new insights into depot- and sex-differences in the developmental origins and growth of adipose tissues as revealed by studies that use new methods, including lineage tracing. Results Variations in fat distribution during normal growth and in response to alterations in nutritional or hormonal status are driven by intrinsic differences in cells found in each adipose depot. Adipose progenitor cells and preadipocytes in different anatomical adipose tissues derive from cell lineages that determine their capacity for proliferation and differentiation. As a result, rates of hypertrophy and hyperplasia during growth and remodeling vary among depots. The capacities of adipose cells are also determined by variations in the expression of key transcription factors and non-coding RNAs. These developmental events are influenced by sex chromosomes, hormonal and nutrient signals that determine the adipogenic, metabolic, and functional properties of each depot. Conclusions These new developments in our understanding of fat distribution provide a sound basis for understanding the association of body shape and health in non-obese and obese men and women.

ContextPeripheral lower body fat is associated with lower cardiometabolic risk. Physiological differences in gluteal compared to abdominal subcutaneous (sc) adipocyte functions are known but the molecular basis for depot differences in adipocyte function is poorly understood.ObjectiveTo identify novel gene regulatory pathways that underlie the heterogeneity of human fat distribution.Design and methodsAbdominal and gluteal adipose tissue aspirates obtained from 35 subjects (age=30±1.6 years; BMI=27.3±1.3kg/m2) were analyzed using Illumina microarrays and confirmed by RT-PCR. The HOTAIR gene was stably transfected into primary cultured human abdominal sc preadipocytes using a lentivirus and effects on adipogenic differentiation were analyzed.ResultsWe identified a long non-coding RNA, HOTAIR that was expressed in gluteal but not in Abd sc adipose tissue. This difference was retained throughout in vitro differentiation and was maximal at day 4. Ectopic expression of HOTAIR in abdominal preadipocytes produced an increase in differentiation as reflected by a higher percentage of differentiated cells, and increased expression of key adipogenic genes including PPARγ and LPL.ConclusionHOTAIR is expressed in gluteal adipose and may regulate key processes in adipocyte differentiation. The role of this lncRNA in determining the metabolic properties of gluteal compared to abdominal adipocytes merits further study.

Sex differences in adipose tissue distribution and the metabolic, endocrine, and immune functions of different anatomical fat depots have been described, but they are incompletely documented in the literature. It is becoming increasingly clear that adipose depots serve distinct functions in males and females and have specific physiological roles. However, the mechanisms that regulate the size and function of specific adipose tissues in men and women remain poorly understood. New insights from mouse models have advanced our understanding of depot differences in adipose growth and remodeling via the proliferation and differentiation of adipose progenitors that can expand adipocyte number in the tissue or simply replace dysfunctional older and larger adipocytes. A limited ability of a depot to expand or remodel can lead to excessive adipocyte hypertrophy, which is often correlated with metabolic dysfunction. However, the relationship of adipocyte size and function varies by depot and sex. For example, femoral adipose tissues of premenopausal women appear to have a greater capacity for adipose expansion via hyperplasia and hypertrophy; although larger, these gluteal-femoral adipocytes remain insulin sensitive. The microenvironment of specific depots, including the composition of the extracellular matrix and cellular composition, as well as cell-autonomous genetic differences, influences sex- and depot-dependent metabolic and growth properties. Although there are some species differences, studies of the molecular and physiological determinants of sex differences in adipocyte growth and function in humans and rodents are both needed for understanding sex differences in health and disease.