Extra-adrenal regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1: physiological regulator and pharmacological target for energy partitioning

Abstract

The major glucocorticoid in man, cortisol, plays important roles in regulating fuel metabolism, energy partitioning and body fat distribution. In addition to the control of cortisol levels in blood by the hypothalamic-pituitary-adrenal axis, intracellular cortisol levels within target tissues can be controlled by local enzymes. 11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) catalyses the regeneration of active cortisol from inert cortisone, thereby amplifying cortisol levels and glucocorticoid receptor activation in adipose tissue, liver and other tissues. 11b-HSD1 is under complex tissue-specific regulation and there is evidence that it adjusts local cortisol concentrations independently of the plasma cortisol concentrations, e.g. in response to changes in diet. In obesity 11b-HSD1 mRNA and activity in adipose tissue are increased. The mechanism of this up-regulation remains uncertain; polymorphisms in the HSD11B1 gene have been associated with metabolic complications of obesity, including hypertension and type 2 diabetes, but not with obesity per se. Extensive data have been obtained in mice with transgenic over-expression of 11b-HSD1 in liver and adipocytes, targeted deletion of 11b-HSD1, and using novel selective 11b-HSD1 inhibitors; these data support the use of 11b-HSD1 inhibitors to lower intracellular glucocorticoid levels and treat both obesity and its metabolic complications. Moreover, in human subjects the non-selective 'prototype' inhibitor carbenoxolone enhances insulin sensitivity. Results of clinical studies with novel potent selective 11b-HSD1 inhibitors are therefore eagerly awaited. The present article focuses on the physiological role of glucocorticoids in regulating energy partitioning, and the evidence that this process is modulated by 11b-HSD1 in human subjects. Glucocorticoids: 11b-Hydroxysteroid dehydrogenase: Energy partitioning:Obesity: Diabetes mellitusThe intracellular enzyme 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) catalyses the interconversion of the active 11-hydroxy glucocorticoid cortisol with its inactive 11-keto metabolite cortisone. 11b-HSD1 is predominantly a reductase in most circumstances, regenerating cortisol from cortisone and thereby increasing intracellular cortisol concentrations. Since 11b-HSD1 is co-localised with glucocorticoid receptors in many cells, including in adipose tissue and liver, it is ideally positioned to amplify local glucocorticoid action (Fig. 1). It follows that chronically increasing 11b-HSD1 activity might increase glucocorticoid receptor activation and thereby promote obesity and its associated metabolic complications, while decreasing 11b-HSD1 may be a strategy to reduce glucocorticoid action selectively in some tissues and thereby reverse the metabolic complications of obesity. In support of this hypothesis transgenic mice overexpressing 11b-HSD1 in adipose tissue develop obesity with all the features of the metabolic syndrome (Masuzaki et al. 2001(Masuzaki et al. , 2003, while 11b-HSD1-knock-out mice areAbbreviations: HPA, hypot...

Adipose tissue expression of 11beta-Hydroxysteroid dehydrogenase type 1 in cushing's syndrome and in obesity

“…However, recent data evidence the opposite, as will be discussed below. 11β-HSD1 seems not to be the cause of the metabolic syndrome, but instead a modulator of energy partitioning (15).…”

“…Thus, 11βHSD1 upregulation in obesity seems not to be a generalized process. In both the whole body and the splanchnic circulation there are no differences between obese and lean subjects regarding cortisol regeneration rates (as measured by [ 2 H4]-cortisol tracer), presumably because an upregulation in adipose tissue is counterbalanced by a downregulation in the liver (15).…”

“…Recent studies suggest that the enzyme is influenced by the nutritional status (15); accordingly, its lack of increase in CS may suggest a protective mechanism against the metabolic complications. Indeed, when the opposite occurs, e.g., weight loss in simple obesity, 11βHSD1 undergoes upregulation (43), although this is not a universal finding (32).…”

“…In addition, recent research has begun to address the question of 11βHSD1 regulation in healthy subjects, and suggest that the enzyme is influenced by the nutritional status (15). A single mixed meal induces a rise in whole body rates of regeneration of cortisol by 11βHSD1 (46), an effect that seems mediated by hyperinsulinemia (47).…”

“…To date approximately eighteen pharmaceutical companies and other organizations have filled patents for 11βHSD1 inhibitors (15). Results of clinical studies with novel potent inhibitors are therefore eagerly awaited.…”