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.

Serum levels of the adipocyte hormone leptin are increased in proportion to body fat stores as a result of increased production in enlarged fat cells from obese subjects. In vitro studies indicate that insulin and glucocorticoids work directly on adipose tissue to upregulate in a synergistic manner leptin mRNA levels and rates of leptin secretion in human adipose tissue over the long term. Thus, the increased leptin expression observed in obesity could result from the chronic hyperinsulinemia and increased cortisol turnover. Superimposed upon the long-term regulation, nutritional status can influence serum leptin over the short term, independent of adiposity. Fasting leads to a gradual decline in serum leptin that is probably attributable to the decline in insulin and the ability of catecholamines to decrease leptin expression, as observed in both in vivo and in vitro studies. In addition, increases in serum leptin occur approximately 4-7 h after meals. Increasing evidence indicates that insulin, in concert with permissive effects of cortisol, can increase serum leptin over this time frame and likely contributes to meal-induced increases in serum leptin. Further research is required to elucidate the cellular and molecular mechanisms underlying short- and long-term nutritional and hormonal regulation of leptin production and secretion.

Short-term studies consistently show that raising the carbohydrate content of the diet increases serum triacylglycerol concentrations. As compared with starches, sugars (particularly sucrose and fructose) tend to increase serum triacylglycerol concentrations by approximately 60%. The magnitude of the effect depends on other aspects of the diet, including the total amount of carbohydrate and the types of fat, carbohydrate, and fiber, but definitive studies to describe the dose-response relations are not available. Longer-term studies show that some high-carbohydrate diets are not associated with increased fasting serum triacylgycerol concentrations. However, sedentary subjects with upper-body and visceral obesity who have the metabolic syndrome tend to be at higher risk for hypertriglyceridemia in response to high-sucrose and high-carbohydrate diets; moderate weight loss mitigates the effect. Hyperinsulinemia or insulin resistance may play a role in promoting higher rates of VLDL synthesis and hypertriglyceridemia in obesity, but the mechanisms remain unclear. The effect of fructose in promoting triacylglycerol synthesis is independent of insulinemia, however. In terms of the long-term effects of diets high in sugars on the risk of cardiovascular disease, available epidemiologic evidence indicates no association of sugars or total carbohydrate intake per se, but high dietary glycemic load is associated with higher serum triacylglycerol concentrations and greater risk of coronary heart disease in women. Studies are needed to delineate the independent effects of dietary sugars and glycemic load on serum triacylglycerol concentrations in lean and obese men and women and to determine whether the elevations in fasting and fed concentrations of serum triacylglycerol with high-carbohydrate and high-sugars diets are associated with increased risk of cardiovascular disease.

We investigated the in vitro regulation of leptin expression in adipose tissue from severely obese women and men before and after culture with insulin (7 nM) and/or dexamethasone (25 nM). Leptin mRNA and leptin secretion were two- to threefold higher in subcutaneous vs. omental adipose tissue before culture. Dexamethasone transiently increased leptin mRNA approximately twofold in both depots after 1 day of culture [ P < 0.01 vs. basal (no hormone control)], but leptin secretion was only increased in omental adipose tissue ( P < 0.005 vs. basal). Insulin did not increase leptin mRNA in either depot but increased leptin secretion ∼1.5- to 3-fold in subcutaneous tissue throughout 7 days of culture ( P < 0.05 vs. basal). The combination of insulin and dexamethasone increased leptin mRNA and leptin secretion approximately two- to threefold in both depots at day 1( P < 0.005 vs. basal or insulin) and maintained leptin expression throughout 7 days of culture. We conclude that insulin and glucocorticoid have depot-specific effects and function synergistically as long-term regulators of leptin expression in omental and subcutaneous adipose tissue from obese subjects.

We have previously shown that exposure of C57BL/6J mice to intermittent hypoxia (IH) leads to 1) hypertriglyceridemia due to upregulation of pathways of lipid biosynthesis, including sterol regulatory element binding protein (SREBP)-1 and stearoyl CoA desaturase (SCD)-1; and 2) hypercholesterolemia due to impaired cholesterol uptake. The goal of the present study was to examine whether hypoxia-inducible factor (HIF)-1 is implicated in changes in lipid metabolism induced by IH. Lean HIF-1alpha (Hif1a)(+/-) mice, which are heterozygous for a null allele at the locus encoding the HIF-1alpha subunit, and their wild-type (WT) Hif1a(+/+) littermates were exposed to IH or control conditions for 5 days. IH increased fasting blood glucose, serum total cholesterol, and high-density lipoprotein-cholesterol, phospholipids, triglycerides (TG), and leptin in mice of both genotypes, whereas serum insulin and interleukin-6 were elevated only in WT mice. The impact of IH on serum TG levels in WT mice was significantly greater than that in Hif1a(+/-) mice (95 +/- 9 vs. 66 +/- 6 mg/dl, P < 0.05), whereas cholesterol and glucose levels were affected independently of genotype. Under hypoxic conditions, mRNA and protein levels of SREBP cleavage-activating protein (SCAP) and SCD-1 and protein levels of nuclear isoform of SREBP-1 in the liver were induced to significantly higher levels in WT mice than in Hif1a(+/-) mice. We conclude that 1) the effect of IH on serum TG levels is mediated through HIF-1, 2) HIF-1 may impact on posttranscriptional regulation of SREBP-1, and 3) the effect of IH on serum cholesterol levels was not altered by partial HIF-1alpha deficiency.

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.

The insulin resistance syndrome X is related to excess intra-abdominal adipose tissue. With lipectomy of >50% of subcutaneous adipose tissue (SQAT) in nonhibernating, adult female Syrian hamsters on high-fat (HF; 50 calorie%) diet and measurements of oral glucose tolerance, oral [(14)C]oleic acid disposal, serum triglycerides, serum leptin, liver fat, perirenal (PR) adipose tissue cellularity, and body composition, we studied the role of SQAT. Sham-operated (S) animals on HF or low-fat (LF; 12.5 calorie%) diets served as controls. After 3 mo there was no visible regrowth of SQAT but HF diet led to similar levels of body weight and body fat in lipectomized and sham-operated animals. Lipectomized (L) animals had more intra-abdominal fat as a percentage of total body fat, higher insulinemic index, a strong trend toward increased liver fat content, and markedly elevated serum triglycerides compared with S-HF and S-LF. Liver and PR adipose tissue uptake of fatty acid were similar in L-HF and S-HF but reduced vs. S-LF, and were inversely correlated with liver fat content and insulin sums during the oral glucose tolerance test. In summary, lipectomy of SQAT led to compensatory fat accumulation implying regulation of total body fat mass. In conjunction with HF diet these lipectomized hamsters developed a metabolic syndrome with significant hypertriglyceridemia, relative increase in intra-abdominal fat, and insulin resistance. We propose that SQAT, via disposal and storage of excess ingested energy, acts as a metabolic sink and protects against the metabolic syndrome of obesity.