**9. 11β –hydroxysteroid dehydrogenase in adipose tissue – relation to obesity and metabolic syndrome**

The metabolic syndrome describes a cluster of risk factors like insulin resistance, type 2 diabetes, dyslipidemia, hypertension [188] and co-occurrence of visceral (abdominal, central) obesity. There are strong morphological and metabolic similarities between the Cushing's syndrome of endogenous or exogenous glucocorticoid excess and the metabolic syndrome [189]. Glucocorticoid excess exerts opposing effects on adipose tissue, with an increase in central fat deposition through stimulation of preadipocyte differentiation, gluconeogenesis and triglyceride synthesis, while peripheral fat is reduced as a result from increased lipolysis and lipoprotein lipase downregulation [108]. Glucocorticoid-induced obesity has been investigated in animal models and in humans. It has been shown that cortisol levels are modestly elevated in patients with the metabolic syndrome and tend to be normal or even reduced in simple obesity [189].

The preponderance of data suggest that the intracellular glucocorticoid reactivation was elevated in adipose tissue of obese rodent models and humans [108, 190]. The enzyme that 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 hormone, insulin and induced weight loss [193-195].

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 137

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

**11. 11β –hydroxysteroid dehydrogenase and pregnancy – role of 11b-HSD type 2 as a protective barrier for fetus to overexposure to glucocorticoids;** 

In mammals, glucocorticoids are important for fetal growth, tissue development and maturation of various organs (surfactant production by the fetal lung, gut enzymes activation and development of the brain and liver). However, supraphysiological levels of glucocorticoids have been shown to cause fetal growth retardation in mammalian models and in human. A number of studies in animal models have examined the effects of prenatal exposure to synthetic glucocorticoids on the fetal development and offspring biology. Maternal glucocorticosteroid treatment reduces birth weight of the offspring and adults exhibit hypertension, hyperinsulinemia, increased hypothalamic–pituitary–adrenal (HPA) axis activity and altered affective behavior [215, 216]). Moreover, human intrauterine growth retardation is associated with high maternal and fetal concentrations of glucocorticoids [217]. Normally, fetal physiological glucocorticoid levels are much lower than maternal levels [218]. The physiological fetoplacental barrier to glucocorticoid exposure is placental 11β-HSD2 that catalyses the rapid conversation of active cortisol and corticosterone to physiologically inert cortisone and corticosterone [219]. 11β-HSD2 acts as a protective barrier to glucocorticoids but a small proportion of maternal glucocorticoid passes through the placenta [220] thus, maternal stress elevates fetal glucocorticoid levels [221]. Different factors are involved in the regulation of placental 11β-HSD2 expression progesterone, estrogen, hypoxia, infection and proinflammatory cytokines reduce placental 11β-HSD2 activity. Conversely, placental 11β-HSD2 activity is stimulated by glucocorticoids, retinoids and leptin [221]. Studies in rats and human indicate that the deficiency in placental 11β-HSD2 activity results in high fetal exposure to maternal glucocorticoids, with subsequent effects on fetal development and birth weight and offspring biology - high plasma cortisol levels, permanent hypertension, hyperglycemia and increased HPA axis activity was present through the adult life [222-224]. Moreover, individuals homozygous for deleterious mutations

**implication in intrauterine growth retardation** 

metabolic complications.

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 influence enzyme activity *in vivo* [186].
