Introduction

Cortisol is the principal glucocorticoid hormone in humans, contributing to homeostatic regulation of basal metabolism and salt and water balance, and modulating the response to stress. Normal adult human adrenal glands secrete around 5-15 mg per day of cortisol. Only a small fraction is excreted as free cortisol in urine, saliva or bile. The rest is cleared by several metabolic pathways before conjugation and urinary excretion. In the past the enzymes responsible for this metabolism of cortisol received little interest, and indeed were considered to be more important for their other activities, including metabolism of exogenous xenobiotics. However, within the last 15 years, major research programmes have developed around these enzymes following recognition that peripheral metabolism of steroids is not only a means of clearing hormone from the circulation but also plays a key role in determining local responses to hormone. By reversible interconversion with inactive metabolites, the highest intracellular cortisol concentrations can be targeted to specific tissues. This, together with modulation of cortisol secretion by the hy-pothalamic-pituitary-adrenal axis and modulation of corticosteroid receptor expression and signalling, provides a complex system of regulating glucocor-ticoid action in a tissue-specific manner (Figure 18.1). In addition, there is interplay between these different determinants of cortisol action since, for example, the rate of metabolic clearance of cortisol by peripheral enzymes influences circulating levels, and thereby affects feedback control of the hy-pothalamic-pituitary-adrenal axis.

Excessive cortisol secretion in Cushing's syndrome is one of the classical causes of secondary obesity. Effects of excess cortisol on adipose tissue are complex, since central (i.e. visceral, abdominal, facial, and nape of neck) fat deposition is increased, while peripheral fat is reduced. This may result from opposing effects of glucocorticoids which on the one hand increase lipolysis and downregulate lipoprotein lipase—thereby liberating free fatty acids from peripheral fat—but on the other hand stimulate pre-adipocyte differentiation and enhance substrate flux in favour of gluconeogenesis and free fatty acid supply to central fat (1,2). Tissue specificity of glucocorticoid action on fat may be explained by regional differences in both glucocorticoid receptor expression (3) and pre-receptor metabolism of cortisol by 11^-hydroxysteroid dehydrogenase type 1 (4). Probably of equal importance in glucocor-ticoid-induced obesity is central stimulation of appetite, mediated by complex interactions between hypothalamic responses to glucocorticoids, leptin and neuropeptide Y (5).

Against this background, the importance of glucocorticoids in obesity has been investigated in animal models and in humans. Early studies focused on glucocorticoid secretion and circulating levels. Recent studies demonstrated altered peripheral metabolism of cortisol in obesity which may have important effects on tissue response to glucocorticoids. In this chapter, we review current knowledge of enzymes which metabolize cortisol,

International Textbook of Obesity. Edited by Per Bjorntorp. © 2001 John Wiley & Sons, Ltd.

Urinary Cortisol Cartoon

Figure 18.1 Determinants of Cortisol activity. The cartoon shows the multiple steps—from the cerebral cortex through hippocampus, hypothalamus, anterior pituitary and adrenal cortex—which regulate cortisol secretion. In addition, it shows that the peripheral response to a given amount of secreted cortisol is determined by the balance between peripheral cortisol clearance, sequestration—in corticosteroid-binding globulin (CBG) or re-versibly inactivated steroid (cortisone)—and interaction with corticosteroid receptors. Other factors then influence the effect of receptor activation (see Figure 18.5). CRH, corticotrophin-re-leasing hormone; ACTH, adrenocorticotrophin

Figure 18.1 Determinants of Cortisol activity. The cartoon shows the multiple steps—from the cerebral cortex through hippocampus, hypothalamus, anterior pituitary and adrenal cortex—which regulate cortisol secretion. In addition, it shows that the peripheral response to a given amount of secreted cortisol is determined by the balance between peripheral cortisol clearance, sequestration—in corticosteroid-binding globulin (CBG) or re-versibly inactivated steroid (cortisone)—and interaction with corticosteroid receptors. Other factors then influence the effect of receptor activation (see Figure 18.5). CRH, corticotrophin-re-leasing hormone; ACTH, adrenocorticotrophin with an emphasis on the 11^-hydroxysteroid dehydrogenases, for which there is strongest evidence of an influence on responses of tissues to glucocorticoids. We also discuss the consequences of deranged activity of these enzymes, and the recent evidence that this is important in subjects with idiopathic obesity. Finally, we discuss the opportunities for therapeutic manipulation of cortisol activity and its relevance to obesity.

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