Increased exposure of fat tissue to cortisol may influence its mass and distribution (107). This is clearly evident in Cushing's syndrome, in which alterations of the hypothalamic-pituitary-adrenal axis leading to cortisol hypersecretion create a phenotype of abdominal obesity, dyslipidemia, insulin resistance, and hypertension (108). Common abdominal obesity obviously shares the latter features, although more subtle alterations of cortisol activity have been documented. Specifically, plasma cortisol levels are normal in abdominal obese subjects (107), but the sensitivity and drive of the hypothalamic-pituitary-adrenal axis have been shown to be increased in some studies (109, 110). Urinary free cortisol levels are also elevated and the cortisol circadian rhythm is flattened (111). In addition to these features, increased peripheral cortisol synthesis by 11b-hydroxysteroid dehydro-genase (HSD) is now clearly emerging as perhaps the most significant hormonal alteration in patients with idiopathic abdominal obesity (112, 113).

Following the discovery of 11b-HSD activity and initial cloning of 11b-HSD types 1 and 2, the classical view was that these enzymes were responsible for cortisol inactivation and glucocorticoid clearance. However, in original purifications, 11b-HSD-1 activity was shown to be bidirectional, either converting active cortisol to inactive cortisone (dehydrogenase activity) or inactive cortisone to active cortisol (oxoreductase activity). In vivo, oxoreductase activity may be predominant over reduc-tase activity, making this enzyme a glucocorticoid-activating enzyme in the tissue where it is expressed (112). Current data obtained in adipose tissue have now clearly shown that 11b-HSD-1, indeed, acts as a local (peripheral) regulator of cortisol action by modulating cellular concentrations of cortisol at the prereceptor level (114, 115).

An important study by Masuzaki et al. (113) demonstrated that increased local cortisol production by 11b-HSD-1 is one of the causal factors in the etiology of visceral obesity. Transgenic mice selectively overexpressing the enzyme in adipose tissue had increased adipose tissue levels of corticosterone (the active glucocorticoid in mice) and developed intra-abdominal obesity that was exaggerated by a high-fat diet (113). The strong conclusion of this article reflects the potential importance of this enzyme in abdominal obesity: "Increased expression of llb-HSD-1 in abdominal adipose tissue may represent a common molecular etiology for visceral obesity and the metabolic syndrome" (113).

In humans, only a few studies have tried to relate peripheral cortisol homeostasis and llb-HSD-1 to abdominal obesity phenotypes. Although some studies on urinary cortisol metabolites support a critical role for llb-HSD-1 in abdominal obesity, results on the enzyme itself are not unanimous. Some studies examining activity and mRNA abundance of the enzyme in whole adipose tissue samples have found increased levels in obesity (107, 116-119). However, data from Tomlinson have shown no association between either omental or subcutaneous adipose tissue llb-HSD-l activity or mRNA and BMI in women (120). This study also showed no difference in llb-HSD-l expression in omental compared with subcutaneous adipose tissue (120). The inconsistent nature of the fat depot difference and the low level association between obesity and llb-HSD-l mRNA observed in women may be considered surprising given the postulated importance of this enzyme as a determining factor for abdominal obesity. However, studies examining llb-HSD-l activity in cultured preadipose cells generated larger depot differences and stronger correlations with obesity (120). Other in vitro evidence regarding ll b-HSD-1 in the various cell types of human adipose tissue remains limited, but studies have suggested that in stromal cells that are not yet committed to the adipocyte lineage, llb-HSDl predominantly inactivates cortisol by forming cortisone (dehydrogenase activity). However, in preadipocytes that are committed to the adipocyte lineage, the same enzyme generates active cortisol from cortisone (oxore-ductase activity) (121, 122). Since cortisol inhibits cell proliferation and stimulates cell differentiation, it is currently believed that the predominant inactivation of cortisol in uncommitted stromal cells has a proliferative effect, whereas the generation of active cortisol in committed preadipocytes stimulates fat storage and adipogenesis. Thus, llb-HSD-1 has been suggested to act as a molecular switch regulating the link between cell proliferation and cell differentiation/adipogenesis (122).

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