Excessive glucocorticoid receptor activation, as in Cushing's syndrome, results in central obesity with insulin resistance, type 2 diabetes, dyslipidemia, and hypertension. The pathophysiological contribution of glucocorticoids to idiopathic human obesity and its associated metabolic complications has been the subject of a long debate, dominated by discussion of the inconsistent changes that occur in plasma cortisol levels in obesity. The article by Engeli et al. in this issue of Obesity Research (1) extends an important recent strand of literature that sheds new light on the role of glucocorticoids in obesity, invoking increased intracellular cortisol levels independently of any change in plasma levels. This has stemmed from recognition of the role of 11β-hydroxysteroid dehydrogenase type 1 (11HSD1)1 in adipose tissue.
11HSD1 is an enzyme that catalyzes 11-keto-reductase activity allowing the regeneration of the major endogenous glucocorticoid cortisol from its inactive circulating metabolite cortisone (2). 11HSD1 is most highly expressed in the liver, adipose tissue, and the central nervous system, where it has been proposed to play a crucial role in maintaining adequate levels of cortisol within cells, even at times of low plasma cortisol levels, thereby ensuring adequate activation of glucocorticoid receptors in these key metabolic tissues (3, 4). A potent influence of 11HSD1 on glucocorticoid action has been confirmed in animals. When fed a high-fat diet, 11HSD1 knockout mice have low intracellular glucocorticoid levels and are protected from obesity, diabetes, and dyslipidemia (5, 6). Conversely, transgenic overexpression of 11HSD1 in white adipose tissue produces mice with elevated intracellular glucocorticoids and central obesity, insulin resistance, hypertension, hyperglycemia, and dyslipidemia (7, 8).
Two crucial clinical questions have arisen from the above-mentioned work: 1) does increased intracellular regeneration of cortisol by 11HSD1 contribute to central obesity and its associations in the metabolic syndrome; and 2) would inhibition of 11HSD1 provide a novel therapeutic strategy to combat obesity and its metabolic complications?
Characterizing dysregulation of 11HSD1 in human obesity has not been straightforward. Both cortisol and cortisone are metabolized in the liver to tetrahydro-metabolites. The usual assessment of 11HSD1 in vivo involves measuring the ratio of cortisol/cortisone metabolites in urine by mass spectrometry. This ratio has been reported to be increased, decreased, or unaltered in obese subjects (9, 10, 11, 12, 13, 14, 15). However, the cortisol/cortisone metabolite ratio is influenced by many potential confounders, such as, in particular, the activity of hepatic A-ring reductases (16). Moreover, it has emerged that dysregulation of 11HSD1 in obesity is tissue-specific. Conversion of cortisone after oral administration to cortisol in peripheral plasma, reflecting first pass metabolism by hepatic 11HSD1, is impaired in obesity (11, 12, 14). In contrast, in subcutaneous abdominal adipose tissue, 11HSD1 activity is increased both in vivo and in vitro (12, 14, 16, 17, 18). Further studies, including that described by Engeli et al. (1), have confirmed that the increased 11HSD1 activity in biopsies is accompanied by increased 11HSD1 mRNA (16, 17, 18, 19). By analogy, as in the transgenic mouse with 3-fold overexpression of 11HSD1 in adipose tissue (7), one would expect a “Cushingoid” phenotype to result from the similar magnitude of increase in adipose 11HSD1 documented in human obesity. Interestingly, although increased subcutaneous adipose 11HSD1 is associated with insulin resistance in obesity, it is not specifically linked with visceral adiposity or with hypertension; in these respects, mice and men may differ, but it remains to be determined whether 11HSD1 mRNA or activity is increased in omental adipose tissue in obese subjects (20).
The mechanisms underlying increased adipose 11HSD1 in obesity are uncertain. Transcription of 11HSD1 is highly regulated, including by many factors that are altered in obesity (e.g., cytokines, sex steroids, growth hormone, insulin, peroxisome proliferator-activated receptor agonists, etc.) (21). The accompanying article by Engeli et al. (1) describes no change in adipose 11HSD1 mRNA after weight loss, suggesting a constitutive abnormality. In contrast, however, in obese Zucker rats and ob/ob mice, the down-regulation of hepatic 11HSD1 is reversible with other manipulations that induce weight loss (22, 23). Attempts to date to link 11HSD1 genotype with obesity have not been successful (24, 25), although, arguably, the intermediate phenotypes (i.e., anthropometric measurements or urinary cortisol/cortisone metabolite ratios) employed are too insensitive to allow clear inferences about the influence of known polymorphisms in the 11HSD1 gene.
As a therapeutic target, 11HSD1 inhibition shows considerable promise. It offers a key advantage over other strategies for manipulating glucocorticoid action, in that circulating cortisol levels and the response to stress are not impaired. Initial studies with the nonselective inhibitor carbenoxolone have shown enhanced hepatic insulin sensitivity both in healthy controls and in patients with type 2 diabetes (3, 26). However, carbenoxolone seems to be a more effective inhibitor of hepatic than adipose 11HSD1 (27). In obese rats and humans, hepatic 11HSD1 is down-regulated, and the incremental effect of carbenoxolone may be lost. Thus, effective inhibition of adipose 11HSD1 may be required in obese patients to obtain useful therapeutic benefits.
11HSD1 inhibition has been pursued by several pharmaceutical companies. Indeed, Amgen recently announced a down payment of $86 million to Biovitrum to enter a deal to exploit Biovitrum's arylsulfonamidothiazole 11HSD1 inhibitors, one of which is currently in a Phase II trial for type 2 diabetes. Published data in mice suggest that arylsulfonamidothiazoles, like carbenoxolone, are effective in enhancing hepatic insulin sensitivity and lowering blood glucose in diabetes (28, 29).
11HSD1 has the capacity to catalyze both 11keto-reductase and 11β-dehydrogenase reactions in vitro (2, 30). Whether any 11β-dehydrogenase activity is present in adipose tissue in vivo is controversial. An intriguing hypothesis proposes that the directionality of 11HSD1 is determined by availability of NADPH (the reduced form of nicotinamide adenine dinucleotide) cofactor generated within the endoplasmic reticulum by hexose-6-phosphate dehydrogenase (31, 32). This might allow alterations in cortisol/cortisone equilibrium over and above any effect of increased 11HSD1 transcription. A key priority will be to measure 11HSD1 reaction direction in vivo in adipose tissue. To add to this uncertainty, Engeli et al. also report detection of mRNA for 11HSD type 2 in human adipose tissue by real-time PCR and show that this signal is increased in obesity (1). However, other investigators have not found 11HSD2 mRNA in adipose tissue or cultured cells using conventional reverse-transcriptase polymerase chain reaction (4). The type 2 isozyme is an exclusive dehydrogenase that inactivates cortisol. 11HSD2 has been detected in vascular endothelium (33), and there is the possibility of vascular contamination of biopsies. The expression level is ∼30-fold lower than 11HSD1, but 11HSD2 has a higher affinity for cortisol (Kd ∼ 10 nM; where Kd represents the dissociation rate constant) than does 11HSD1 for cortisone (Kd ∼ 10 μM); therefore, 11HSD2 could be important in determining turnover. This observation requires further confirmation.
In summary, 11HSD1 is an exciting potential mediator of the Cushingoid features of obesity and is a topical therapeutic target in the metabolic syndrome.