Glucocorticoid Metabolism: Regulation Of Tissue Specific Responses In Obesity (pp. 85-119)
Authors: Andrew, Ruth; R., Walker, Brian R. (Walker University of Edinburgh Endocrinology )
Abstract: Glucocorticoid hormones are key regulators of carbohydrate and lipid metabolism. They exert their metabolic actions mainly by activating glucocorticoid receptors in tissues such as liver and adipose. Excess glucocorticoids, as in Cushing’s Syndrome, is associated with lipid accumulation, type 2 diabetes mellitus and dyslipidaemia. The clustering of these same features in the general population is referred to as the “Metabolic Syndrome” and it has been proposed that subjects predisposed to developing this syndrome may be suffering from a form of glucocorticoid excess within specific tissues. This review summarises the evidence that glucocorticoid excess in these subjects may be due to alterations in tissue-specific metabolism of glucocorticoids, whereby local metabolism regulates local steroid level by activating or inactivating hormones, in close proximity to their target receptor. Recently much attention has been focussed on the actions of the isozymes of 11â-hydroxysteroid dehydrogenases, in particular the type 1 reductase in regulating concentrations of active glucocorticoids in liver and adipose and its role in regulating homeostatic processes in response to diet. However emerging data suggests that 5á-reductases may also be responsible for generating active glucocorticoids. Here the role of key metabolic enzymes (11â-hydroxysteroid dehydrogenases, 5á-reductases, 5â-reductase, 3á- hydroxysteroid dehydrogenases) in normal physiology is discussed. These mechanisms are then extended to explore the impact of transgenic manipulation of the enzymes in animal models and parallels drawn with congenital human syndromes associated with mutations in the same genes. Current understanding of alterations in enzyme activities and their impact on the aetiology, pathophysiology and prognosis of the Metabolic Syndrome are reviewed. Finally the potential benefits of therapeutic manipulation of these pathways are discussed.