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

Abstract

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 (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 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.

Keywords: 11-beta hydroxysteroid dehydrogenase; Adipokine; Cortisol; Inflammation; Lipogenesis; Lipolysis.

Figure 1. Pleiotropic actions of glucocorticoids in adipose tissue

GCs influence multiple aspects of adipose tissue biology: adipogenesis, metabolism, inflammation and adipokine production. Arrows indicates the direction of reported changes in experiments conducted under different conditions. Specifying these conditions, as discussed in the text, is essential for developing a full understanding of GC action.

Figure 2. Glucocorticoids simultaneously increase pathways of TG synthesis and breakdown

A. GCs especially when added in the presence of insulin, mimicking the fed state, induce the expression of genes involved in lipid uptake (LPL), TG synthesis (LIPIN, AGPAT, DGAT1) and de novo lipogenesis (ACC, FAS). GCs also increase the expression of genes involved in TG hydrolysis (ATGL, HSL, MGL). GC induction of PCK1 expression is likely to play a role in glyceroneogenesis, contributing to TG synthetic pathway. B. GCs increase lipid turnover in adipose tissue. While GCs are widely cited as lipolytic and thought to increase systemic FFA, they also increase lipid uptake and TG synthesis. Factors that tip this balance toward TG synthesis in a depot-dependent manner may lead to hypertrophy of existing adipocytes and hence affect regional adiposity.