Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

Andreas Stomby Ruth Andrew Brian R. Walker Tommy Olsson 0 ) Endocrinology Unit, BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh , 47 Little France Crescent, Edinburgh, Scotland EH164TJ , UK Cushing's syndrome, caused by increased production of cortisol, leads to metabolic dysfunction including visceral adiposity, hypertension, hyperlipidaemia and type 2 diabetes. The similarities with the metabolic syndrome are striking and major efforts have been made to find obesityassociated changes in the regulation of glucocorticoid action and synthesis, both at a systemic level and tissue level. Obesity is associated with tissue-specific alterations in glucocorticoid metabolism, with increased activity of the glucocorticoidregenerating enzyme 11-hydroxysteroid dehydrogenase type 1 (11HSD1) in subcutaneous adipose tissue and decreased conversion of cortisone to cortisol, interpreted as decreased 11HSD1 activity, in the liver. In addition, genetic manipulation of 11HSD1 activity in rodents can either induce (by overexpression of Hsd11b1, the gene encoding 11HSD1) or prevent (by knocking out Hsd11b1) obesity and metabolic dysfunction. Taken together with earlier evidence that non-selective inhibitors of 11HSD1 enhance insulin sensitivity, these results led to the hypothesis that inhibition of 11HSD1 might be a promising target for treatment of the metabolic syndrome. Several selective 11HSD1 inhibitors have now been developed and shown to improve metabolic dysfunction in patients with type 2 diabetes, but the small magnitude of the glucose-lowering effect has precluded their further commercial development. Brian R. Walker and Tommy Olsson share senior authorship of this review. - Cushings syndrome is caused by over-exposure to glucocorticoids and leads to central fat (i.e. visceral adipose tissue) accumulation, hyperlipidaemia, hypertension and insulin resistance [1]. This is associated with increased risk for cardiovascular disease [2]. The similarities between Cushings syndrome and obesity with metabolic complications led to the hypothesis that increased cortisol levels could cause the metabolic syndrome. Apparently in support of this hypothesis, excretion of glucocorticoid metabolites in urine is elevated in obese people [3], suggesting an increased glucocorticoid production rate, and this has been verified by stable isotope tracer studies in patients with obesity and type 2 diabetes [4]. Moreover, obesity has been associated with impaired negative feedback suppression of the hypothalamic pituitary adrenal axis (HPAA) (by dexamethasone suppression tests) in some [5], but not all [6], studies, and with increased stimulation of cortisol production by adrenocorticotrophic hormone (ACTH) [7]. However, circulating cortisol levels are normal or slightly decreased in the morning in obese individuals [8]. This combination of increased urinary cortisol metabolite excretion with a hyperdynamic HPAA and normal cortisol levels is most likely to be explained by increased peripheral metabolic clearance of cortisol. Indeed, increased cortisol clearance has been documented repeatedly in obesity [4, 911]. In the 1990s, this led us to explore whether altered peripheral cortisol metabolism might have any role in driving cortisol excess within tissues and hence the metabolic complications of obesity. Over 60 years ago it was shown that cortisone could be converted to cortisol in many rodent organs, particularly in the liver. In the late 1980s the bidirectional enzyme 11hydroxysteroid dehydrogenase (11HSD), functioning both as a reductase (converting cortisone to cortisol) and dehydrogenase (converting cortisol to cortisone), was cloned from rat liver [12]. Later, with the cloning of 11HSD type 2 [13], the liver isozyme was labelled as 11HSD type 1 (11HSD1). In disrupted cells, 11HSD1 acts predominantly as a dehydrogenase, converting cortisol to cortisone [14], but if cells are intact the reductase (cortisone to cortisol) activity is much higher [15, 16]. In rodents and humans, 11HSD1 is mainly expressed in the liver but is present in several other tissues as well, e.g. adipose tissue [16], brain [17], immune cells [18] and, at least in humans, skeletal muscle [19]. By analogy with the role of 11HSD2 in preventing cortisol from accessing mineralocorticoid receptors by conversion to inactive cortisone [20], the hypothesis emerged that 11HSD1 amplifies glucocorticoid receptor activation by converting cortisone to cortisol [21]. This hypothesis was supported by observations that inhibition of 11HSDs with the non-selective inhibitor carbenoxolone resulted in enhanced insulin sensitivity in humans [22] and that deletion of Hsd11b1 (the gene encoding 11 H S D 1 ) i n m i c e r e s u l t e d i n p r o t e c t i o n f r o m hyperglycaemia [23], consistent with reduced local glucocorticoid action. Its potential relevance in obesity was thrown into sharp relief by the observation from Paul Stewarts group that 11HSD1 converts cortisone to cortisol in vitro in cells from human visceral adipose tissue [16]. Historically, 11HSD1 activity has been measured by the ratio of cortisol/cortisone metabolites in urine, or by the rate of appearance of cortisol in plasma after the oral administration of cortisone. The first studies testing the hypothesis that 11HSD1 is dysregulated in obesity suggested increased urinary cortisol/cortisone metabolite ratios in urine [3], but paradoxically, decreased first pass conversion of cortisone to cortisol in the liver [24] in obese compared with lean people. A crucial insight was provided by parallel studies in rodents. In obese Zucker rats, tissue-specific dysregulation of 11HSD1 was found, with reduced expression in the liver accompanied by increased expression in subcutaneous adipose tissue [25]. It was hypothesised that 11HSD1 may be upregulated in adipose tissue in obesity, while simultaneously downregulated in the liver, with the overall balance between cortisol and cortisone determined by a combination of liver and adipose tissue enzyme activities. To test this we conducted a cross-sectional study in lean and obese men and obtained subcutaneous adipose tissue biopsies. The obese men had increased 11HSD1 activity in subcutaneous adipose tissue and decreased first pass conversion of orally administered cortisone to cortisol in plasma, suggesting decreased hepatic 11HSD1 activity (Fig. 1) [26]. This key observation, subsequently replicated in women [27], suggested that, even though circulating cortisol is not elevated in obesity, more cortisol is generated within adipose tissue by 11HSD1, which may play a part in the development of obesity and its associated comorbidities. Fig. 1 Tissue-specific dysregulation of 11HSD1 in obesity. (a) Plasma cortisol after dexamethasone suppression and oral cortisone. Data are mean SE. (b) In vitro 11HSD1 activity in subcutaneous adipose tissue. Data are mean SE for % conversion of cor (...truncated)