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.