The Journal of Steroid Biochemistry and Molecular Biology
11β-Hydroxysteroid dehydrogenase type 1 is an important regulator at the interface of obesity and inflammation
Introduction
The striking resemblances between symptoms of hypercortisolism (also known as Cushing syndrome) and symptoms of the metabolic syndrome have initiated intensive investigations on the potential aetiological role of glucocorticoids in the current obesity epidemic. Glucocorticoids (cortisol and cortisone in man, corticosterone and dehydrocorticosterone in rodents) are synthesized in and secreted from the zona fasciculata of the adrenal gland, under control of adrenocorticotropic hormone (ACTH, also known as corticotropin) which is secreted from the anterior pituitary gland. The secretion of ACTH in turn is regulated by vasopressin and corticotropin-releasing hormone (CRH), both peptide hormones that originate in the hypothalamus. This complex set of hormone interactions and regulations is often referred to as the hypothalamus–pituitary–adrenal (HPA) axis.
Serum glucocorticoids readily pass cell membranes and exert their intracellular functions by binding to the glucocorticoid receptor (GR), a ligand-activated nuclear receptor which regulates the expression of a plethora of genes involved in various physiological processes including energy metabolism and inflammation. However, this receptor only binds the reduced form, e.g. cortisol, with high affinity. Two microsomal enzymes collectively referred to as the 11β-hydroxysteroid dehydrogenase (11β-HSD) system interconvert receptor-active cortisol and inert cortisone and, through intracellular cortisol amplification or inactivation, represent an additional regulatory step prior to glucocorticoid action (Fig. 1).
Hence, glucocorticoid functions are subject to several levels of regulation, and an exaggerated glucocorticoid response – as observed in the metabolic syndrome – might be a result of excess glucocorticoid secretion by the HPA axis, increased intracellular GR density or deregulated intracellular glucocorticoid prereceptor metabolism by the 11β-HSD system. During the last 10 years, evidence has accumulated that strongly argues for an aetiological role of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in obesity and the metabolic syndrome [1], [2], [3], [4], [5], [6], [7]. At the same time, increasingly more studies support a function for 11β-HSD1 in inflammation [8], [9], [10], [11], [12], [13], [14], [15]. Interestingly, adiposity has been shown to associate with an increase of macrophage numbers and pro-inflammatory cytokines in adipose tissue [16], [17], [18], [19]. Hence, 11β-HSD1 might function as an important regulator at the interface of inflammation and obesity.
Within this review, we will present support for this hypothesis in form of a comprehensive list of GR-regulated genes with implication in metabolic/inflammatory disease and a summary of the thus far published transcription factors/agonists with known implication in energy metabolism and inflammation that modulate intracellular 11β-HSD1 activity.
Section snippets
Glucocorticoids and glucocorticoid receptor in the aetiology of the metabolic syndrome
Glucocorticoid treatment of inflammatory diseases or excess secretion of cortisol by the adrenal cortex results in the Cushing syndrome, with symptoms closely reflecting the metabolic syndrome, i.e. obesity, insulin resistance, hypertension and an unfavourable lipid and lipoprotein profile [20]. Furthermore, monogenic rodent models for the metabolic syndrome, e.g. the leptin-deficient ob/ob mouse or the leptin-resistant Zucker rat, display overall increased secretion of glucocorticoids [21],
The 11β-HSD system in glucocorticoid metabolism
The intracellular bioavailability of active glucocorticoids is modulated by the microsomal 11β-hydroxysteroid dehydrogenases which interconvert cortisol and cortisone in man, and corticosterone and 11-dehydrocorticosterone in rodents (Fig. 1) [50], [51], [52]. 11β-hydroxysteroid dehydrogenase type 1 mainly acts as an NADPH-dependent reductase, due to its colocalization with hexose-6-phosphate dehydrogenase in the endoplasmic reticulum [53], [54]. In contrast, 11β-hydroxysteroid dehydrogenase
Conclusions
For a long time, glucocorticoid excess has been known to cause obesity. From all possible regulatory levels of glucocorticoid action including the HPA axis, intracellular GRα density, and prereceptor metabolism, the latter, in the form of the enzyme 11β-HSD1, has emerged as the most convincing determinant. 11β-HSD1 is thus nowadays recognized as a promising drug target in the current obesity epidemic. Through amplification of receptor-active glucocorticoid, 11β-HSD1 enhances the glucocorticoid
Acknowledgements
Work on 11β-HSD1 in our laboratory is funded by the German Federal Ministry of Education and Research (0315397A) and the Deutsche Forschungsgemeinschaft (MA 1704/5-1).
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