**10. 11β-HSD and metabolite syndrome - clinical importance**

Based on human data and genetic models, 11β-HSD1 seems to be cause and promising pharmaceutical target for the treatment of metabolic disease. In mice, the increased enzyme activity in adipose tissue enhances local glucocorticoid levels and produces a metabolic syndrome [196], whereas the decreased enzyme activity protects against obesity and the metabolic syndrome [200, 201]. In human, 11β-HSD1 expression is elevated in adipose tissue in obesity [206], whereas inhibition of 11β -HSD1 enhances insulin sensitivity and provides a new approach to treat type 2 diabetes [207-209]. Polymorphisms in the HSD11B1 gene that encodes 11β-HSD1 have been associated with type 2 diabetes [203] and hypertension [204, 205]. On the other hand, a polymorphism that predicts 11β-HSD1 deficiency may protect against obesity and its metabolic consequences because of impaired regeneration of cortisol in adipose tissue [180]. 11β-HSD1 inhibition is a tempting target for treatment of the metabolic syndrome and its complications. Selective 11beta-HSD1 inhibitors in rodents cause weight loss, improve insulin sensitivity and delay progression of cardiovascular disease [210-212]. Pharmacological inhibition of 11b-HSD1 with the anti-ulcer drug carbenoxolone has provided evidence that cortisol regeneration influences insulin sensitivity, particularly glycogen turnover in healthy human subjects and in patients with type 2 diabetes [207, 208]. This corroborated the notion that the enzyme may be an attractive option to treat the metabolic disease [108, 190, 202, 212, 213]. Moreover, 11β-HSD1 gene knock-out (11β-HSD1-/-) mice exhibited cardioprotective phenotype with improved glucose tolerance and lipid profile, reduced weight and visceral fat accumulation in condition of chronic high-fat feeding [190, 200, 201, 214]. These data support the beneficial effects of 11β-HSD1 inhibitors to lower intracellular glucocorticoid levels and to treat both obesity and its metabolic complications.

136 Dehydrogenases

mediates this activation, locally within tissues, is 11β-HSD1 that converts inactive metabolite cortisone to active cortisol, thereby amplifying local glucocorticoid action [104]. 11β-HSD1 expression in adipose tissue was first reported by Monder and White [144] and it is thought to be a dehydrogenase. Studies in leptin-resistant obese rats revealed that obesity was associated with an increase in 11β-HSD1 in abdomenal adipose tissue [191]. In human subcutaneous abdominal adipose tissue, 11β-HSD1 activity is increased both *in vivo* and *in vitro* and the enhanced 11β-HSD1 activity in biopsies is accompanied by elevated 11β- HSD1 mRNA levels [108]). It is interesting to note, that increased subcutaneous adipose 11β-HSD1 is associated with insulin resistance in obesity, but it is not linked specifically with visceral fat accumulation or hypertension [192]. The mechanisms underlying the increase in adipose 11β-HSD1 activity in obesity and metabolic syndrome are still not fully inderstood. 11β-HSD1 transcription is regulated by many factors like cytokines, sex steroids, growth

The key question is whether increased 11β-HSD1 in adipose tissue is a cause or a consequence of obesity and it is associated with metabolic syndrome. In order to determine this, mice over-expressing 11β-HSD1 selectively in adipose tissue have been generated, using the adipocyte fatty acid binding protein (aP2) promoter [196, 197]. The adiposeselective 11β-HSD1 transgenic mice exhibited elevated intra-adipose, but not systemic corticosterone levels, as well as the major features of the metabolic syndrome-abdominal obesity, hyperglycaemia, insulin resistance, dyslipidaemia and hypertension. Conversely, transgenic mice with overexpression of 11β-HSD1 in liver showed an attenuated metabolic syndrome with modest insulin resistance and hypertriglyceridemia, hypertension and fatty liver, but with normal body weight [198]. 11β-HSD1-knock-out mice fed on a high-fat diet are protected from obesity and metabolic complications [199-201]. Recently, polymorphisms in *HSD11B1*, the gene encoding 11β-HSD1, have been associated with components of the metabolic syndrome [186, 202-205]. Moreover, subjects with single nucleotide polymorphisms (SNPs) in *HSD11B1* gene exhibit increased adipose 11β-HSD1 expression and increased whole-body 11β-HSD1 activity, associated with increased prevalence of the metabolic syndrome. These findings strengthen the view that variations in 11β-HSD1 activity influence the metabolic profile and provide a new evidence that *HSD11B1* gene

hormone, insulin and induced weight loss [193-195].

influence enzyme activity *in vivo* [186].

**10. 11β-HSD and metabolite syndrome - clinical importance** 

Based on human data and genetic models, 11β-HSD1 seems to be cause and promising pharmaceutical target for the treatment of metabolic disease. In mice, the increased enzyme activity in adipose tissue enhances local glucocorticoid levels and produces a metabolic syndrome [196], whereas the decreased enzyme activity protects against obesity and the metabolic syndrome [200, 201]. In human, 11β-HSD1 expression is elevated in adipose tissue in obesity [206], whereas inhibition of 11β -HSD1 enhances insulin sensitivity and provides a new approach to treat type 2 diabetes [207-209]. Polymorphisms in the HSD11B1 gene that encodes 11β-HSD1 have been associated with type 2 diabetes [203] and hypertension [204, 205]. On the other hand, a polymorphism that predicts 11β-HSD1 deficiency may protect
