The role of glucocorticoid action in the pathophysiology of the Metabolic Syndrome

Abstract

Glucocorticoids are stress hormones that modulate a large number of physiological actions involved in metabolic, inflammatory, cardiovascular and behavioral processes. The molecular mechanisms and the physiological effects of glucocorticoids have been extensively studied. However, the involvement of glucocorticoid action in the etiology of the Metabolic Syndrome has not been well appreciated. Recently, accumulating clinical evidence and animal genetics studies have attracted growing interest in the role of glucocorticoid action in obesity and insulin resistance. This review will discuss the metabolic effects in the context of glucocorticoid metabolism and establish the association of glucocorticoid action with the features of the Metabolic Syndrome, especially obesity and insulin resistance. Special discussions will be focused on corticosteroid-binding globulin and 11beta-hydroxysteroid dehydrogenase type 1, two proteins that mediate glucocorticoid action and have been implicated in the Metabolic Syndrome. Due to the complexities of the glucocorticoid biology and the Metabolic Syndrome and limited space, this review is only intended to provide a general link between the two areas with broad rather than in-depth discussions of clinical, pharmacological and genetic findings.

Figure 1

Glucocorticoid metabolism. The secretion of glucocorticoids by the adrenal gland is regulated by the HPA axis via secretion of ACTH. The main plasma cortisol (F) is protein bound with 4–5% free fraction. The plasma cortisone (E) is in the free unbound form. The equilibrium of cortisol and cortisone between the plasma and tissues are illustrated with the dotted bidirectional arrows. Tissue-specific GC metabolism are also depicted. GCs are metabolized primarily in liver and the metabolites are excreted in the urine. Only tissues relevant to the Metabolic Syndrome are shown. THE, tetrahydrocortisone; THF, tetrahydrocortisol.

Figure 2

The link between the metabolic effects of glucocorticoids and the features of the Metabolic Syndrome. The major effects in different tissues are summarized and the potential physiological links to the Metabolic Syndrome are shown.