Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue

“In contrast, adipose mRNA-encoding resistin, which may lead to insulin resistance (Steppan et al., 2001), is reduced in transgenic adipose tissue, perhaps as a consequence of glucocorticoid excess (Viengchareun et al., 2002).”

“Thus, transgenic adipose tissue has decreased expression of the insulin-sensitising factor adiponectin (acrp30, adipoQ) (Yamauchi et al., 2002) and increased expression of TNF , an adipose cytokine that causes insulin resistance (Hotamisligil et al., 1993).”

“Of the latter, the hippocampus, a part of the limbic system, has attracted much attention, as it contains a very high density of intracellular receptors for glucocorticoids and is a key locus for glucocorticoid effects upon memory and perhaps mood (de Kloet, 1991; McEwen, 1999).”

“aP2–11 -HSD1 transgenic mice show adipocyte hypertrophy but not hyperplasia (Masuzaki et al., 2001).”

“The hippocampus appears to act as a “brake” upon the HPA axis, since lesions interfere with glucocorticoid feedback control of HPA stress responses (Jacobson and Sapolsky, 1991).”

“11 -HSD2 functions predominantly to exclude glucocorticoids from intrinsically nonselective MR in vivo (Edwards et al., 1988; Funder et al., 1988).”

“While this level is lower than diurnal peak cortisol of 400–600 nmol/l, cortisone is largely unbound, while 95% of cortisol is sequestered by binding to plasma proteins such as CBG (Dunn et al., 1981).”

“11 -HSD2 functions predominantly to exclude glucocorticoids from intrinsically nonselective MR in vivo (Edwards et al., 1988; Funder et al., 1988).”

“These respond to glucocorticoids in a similar manner to adipose tissue in vivo (MacDougald et al., 1994; MacDougald and Lane, 1995).”

“These receptors are essential for life, since knockout (KO) of either by homologous recombination in mice is lethal at (for GR) or soon after (for MR) birth (Cole et al., 1995; Berger et al., 1998).”

“The metabolic syndrome (Reaven’s syndrome X; the insulin resistance syndrome) describes a constellation of cardiovascular risk factors — specifically, insulin resistance, type 2 diabetes, dyslipidemia, and hypertension (Reaven, 1993,2002).”

“Importantly, the mice have more-than-adequate, stress-induced HPA axis responses (Harris et al., 2001) and do not exhibit hypoglycaemia with prolonged fasting (Kotelevtsev et al., 1997).”

“In terms of isozymes, 11 -HSD1, but not 11 -HSD2, mRNA is expressed in rat white (epididymal) adipose tissue (WAT) (Napolitano et al., 1998) and in human adipose tissue (Bujalska et al., 1997; Sun et al., 1997; Paulmyer-Lacroix et al., 2002).”

“…lipoprotein lipase — thereby liberating free fatty acids (FFAs) from peripheral fat — but, on the other hand, stimulate preadipocyte differentiation and enhance substrate flux in favour of gluconeogenesis and triglyceride synthesis in central fat (Samra et al., 1998; Andrews and Walker, 1999).”

“Subsequently, two 11 -HSD isozymes have been characterised, isolated, and their cDNAs cloned, the products of distinct and only distantly related genes (reviewed in White et al., 1997; Stewart and Krozowski, 1999; Seckl and Walker, 2001).”

“Subsequently, two 11 -HSD isozymes have been characterised, isolated, and their cDNAs cloned, the products of distinct and only distantly related genes (reviewed in White et al., 1997; Stewart and Krozowski, 1999; Seckl and Walker, 2001).”

“C. 11 -HSD TYPE 2 11 -HSD type 2 is a high-affinity (low nM Km for cortisol), nicotinamide adenine dinucleotide (NAD)-dependent dehydrogenase that rapidly converts active cortisol to inert cortisone (Albiston et al., 1994; Brown et al., 1996b).”

“In contrast, in subcutaneous abdominal adipose tissue, 11 -HSD1 activity is increased both in vivo and in vitro (Rask et al., 2001,2002; Lindsay et al., 2003; Wake et al., 2003).”

“Both are commensurate with the effects of glucocorticoid excess (Fasshauer et al., 2002; Viengchareun et al., 2002).”

“Inhibition of this enzyme with liquorice (Stewart et al., 1987) or disruption of the 11 -HSD2 gene in mice (Kotelevtsev et al., 1999) or humans (Mune et al., 1995; Dave-Sharma et al., 1998) leads to the syndrome of apparent mineralocorticoid excess (AME).”

“For the metabolic syndrome, case-control and cross-sectional studies have suggested that high blood pressure associates with somewhat elevated cortisol concentrations (in blood, saliva, or urine) (Watt et al., 1992; Filipovsky et al., 1996; Stolk et al., 1996; Rosmond et al., 1998; Walker et al., 1998; Fraser et al.,…”

“Subsequently, two 11 -HSD isozymes have been characterised, isolated, and their cDNAs cloned, the products of distinct and only distantly related genes (reviewed in White et al., 1997; Stewart and Krozowski, 1999; Seckl and Walker, 2001).”

“Moreover, liver 11 -HSD1 is downregulated in obesity, so that the incremental effect of inhibition may be smaller in the obese (Stewart et al., 1999; Rask et al., 2001,2002).”

“…to stimuli such as acute stress, CRH/AVP (Pasquali et al., 1999), adrenergic manipulations (Pasquali et al., 2000), hypoglycaemia, or a standard meal (Marin et al., 1992; Hautanen and Adlercreutz, 1993) is enhanced in idiopathic obesity, particularly visceral obesity (Pasquali et al., 2000).”

“However, 11 -HSD1 is widely expressed in other tissues in humans (Ricketts et al., 1998) and rodents (Moisan et al., 1990b), including liver (Agarwal et al., 1989; Tannin et al., 1990), adipose tissue (Bujalska et al., 1997; Napolitano et al., 1998), lung (Hundertmark et al., 1993), skeletal…”

“The hypertension is associated with renin-angiotensin-aldosterone system (RAAS) activation and is strikingly sensitive to low doses of an angiotensin II receptor antagonist (Masuzaki et al., 2003).”

“These receptors are essential for life, since knockout (KO) of either by homologous recombination in mice is lethal at (for GR) or soon after (for MR) birth (Cole et al., 1995; Berger et al., 1998).”

“Moreover, liver 11 -HSD1 is downregulated in obesity, so that the incremental effect of inhibition may be smaller in the obese (Stewart et al., 1999; Rask et al., 2001,2002).”

“For the metabolic syndrome, case-control and cross-sectional studies have suggested that high blood pressure associates with somewhat elevated cortisol concentrations (in blood, saliva, or urine) (Watt et al., 1992; Filipovsky et al., 1996; Stolk et al., 1996; Rosmond et al., 1998; Walker et al., 1998; Fraser et al.,…”

“A-ring reductases (5 - and - ) are activated in both animal (Livingstone et al., 2000a) and human obesity (Andrew et al., 1998,2002).”

“Similarly, insulin resistance and glucose intolerance are associated with higher circulating cortisol levels (Phillips et al., 1998; Reynolds et al., 2001).”

“, 2002), although this sex is typified by a more-android adipose distribution! Several studies suggest that individuals with common GR polymorphisms demonstrate HPA axis abnormalities in addition to a peripheral phenotype of increased adiposity, insulin resistance, and hypertension (Bjorntorp et al., 1999; Rosmond et…”

“PPAR ligands cause fat redistribution to the periphery, which may underpin the favourable morphology seen (Kelly et al., 1999; Sewter et al., 2002).”

“11 -HSD2 inhibition also reduces fetal growth and alters tissue maturation (Lindsay et al., 1996a,b).”

“C. 11 -HSD TYPE 2 11 -HSD type 2 is a high-affinity (low nM Km for cortisol), nicotinamide adenine dinucleotide (NAD)-dependent dehydrogenase that rapidly converts active cortisol to inert cortisone (Albiston et al., 1994; Brown et al., 1996b).”

“For the metabolic syndrome, case-control and cross-sectional studies have suggested that high blood pressure associates with somewhat elevated cortisol concentrations (in blood, saliva, or urine) (Watt et al., 1992; Filipovsky et al., 1996; Stolk et al., 1996; Rosmond et al., 1998; Walker et al., 1998; Fraser et al.,…”

“…transfected with 11 -HSD1 cDNA or in primary cells in culture show that in most, if not all, intact cells and organs, this enzyme is a predominant 11- ketoreductase, reactivating inert cortisone into cortisol (Low et al., 1994a; Hundertmark et al., 1995; Jamieson et al., 1995; Rajan et al., 1996).”

“It has been proposed that the level of 11 -HSD1 mRNA expression and total protein may not be the most-important determinant of net cortisol generation from cortisone, since the balance between reductase and dehydrogenase activities may be crucially dependent upon cofactor generation by hexose-6-phosphate dehydrogenase…”

“Such indirect studies, as well as the use of relatively nonselective, liquorice-based inhibitors (Walker et al., 1995; Andrews et al., 2003), indicate that impaired activity of 11 -HSD1 in liver is associated with features of reduced glucocorticoid action and increased insulin sensitivity in…”

“Higher morning plasma cortisol concentrations and increased responsiveness to corticotropin (ACTH) occur in adults having the additional cardiovascular risk factor of low birth weight (Phillips et al., 1998,2000; Levitt et al., 2000; Reynolds et al., 2001).”

“UCP-2 is downregulated by glucocorticoids (Udden et al., 2001) and upregulated by PPAR activation (Kelly et al., 1998), so its induction in the 11 -HSD1 null mouse adipose tissue is not unexpected.”

“Stable isotope glucose tracers have been used to demonstrate that, in lean patients with type 2 diabetes, carbenoxolone inhibits hepatic glucose production (Andrews et al., 2003).”

“These agents inhibit 11 -HSD1 and enhance insulin action in liver, decreasing PEPCK and glucose-6-phosphatase expression and lowering blood glucose concentrations in KKAY diabetic and ob/ob obese mice (Alberts et al., 2002,2003).”

“Thus, in humans, cultures of omental stromal cells have more 11 -HSD1 than subcutaneous stromal cells (Bujalska et al., 1999).”

“In an analogous action, 11 -HSD2 in placenta and fetal tissues appears to exclude glucocorticoids from GR in utero (Benediktsson et al., 1997; Seckl et al., 2000).”

“Variation in density or function of coactivators and corepressors may underlie aspects of interindividual variation in glucocorticoid sensitivity (Li et al., 2003).”

“glucocorticoid-dependent gene transcription have been inconclusive (Lindsay et al., 2003; Wake et al., 2003).”

“glucocorticoid-dependent gene transcription have been inconclusive (Lindsay et al., 2003; Wake et al., 2003).”

“C. 11 -HSD IN THE BRAIN IN OBESITY While not the main object of this review (for details of 11 -HSDs in the CNS, see Seckl, 1997; Yau and Seckl, 2001), specific CNS changes in 11 -HSDs in obese rodents have been reported that add to the complexity of tissue-specific dysregulation.”

“Recently, a new, potent, nonsteroidal class of selective inhibitors of 11 HSD1 has been described, the arylsulfonamidothiazoles (Barf et al., 2002).”

“Thus, while PPAR ligands such as thiazolidinediones downregulate 11 -HSD1 in 3T3 cells in vitro and in epididymal fat in mice in vivo (Berger et al., 2001), the same was not observed in lean or obese Zucker rats (Livingstone et al., 2000b).”

“While some data in humans suggest that plasma cortisol is higher during the evening nadir in obesity, flattening the diurnal variation (Ljung et al., 1996; Rosmond et al., 1998), evidence is lacking for marked elevations of basal plasma cortisol in obesity.”

“For example, patients with essential hypertension or type 2 diabetes have enhanced tissue sensitivity to glucocorticoids, as measured by the intensity of dermal vasoconstriction following topical application of beclomethasone (Walker et al., 1996,1998; Andrews et al., 2002).”

“However, 11 -HSD1 is widely expressed in other tissues in humans (Ricketts et al., 1998) and rodents (Moisan et al., 1990b), including liver (Agarwal et al., 1989; Tannin et al., 1990), adipose tissue (Bujalska et al., 1997; Napolitano et al., 1998), lung (Hundertmark et al., 1993), skeletal…”

“Indeed, the lifespan of this model is apparently normal and the animals resist the normal glucocorticoid-associated decline of memory and other cognitive processes with ageing (Yau et al., 2001).”

“For example, carbenoxolone, which inhibits both renal 11 -HSD2 and hepatic 11 -HSD1, does not alter the ratio of cortisol/cortisone metabolites (Stewart et al., 1990).”

“Indeed, when adipocytes were cultured, there was an inverse correlation between 11 - HSD1 and obesity (Tomlinson et al., 2002), although the effects of anaesthesia and/or stress on the subsequent pattern of gene expression and 11 -HSD1 activity and direction are difficult to anticipate.”

“Importantly, in humans, GR mRNA levels in skeletal muscle correlate with insulin sensitivity and blood pressure (Reynolds et al., 2002; Whorwood et al., 2002).”

“Moreover, dermal (vascular) sensitivity to GR agonists correlates with component disorders of the metabolic syndrome (Walker et al., 1996,1998; Andrews et al., 2002) and is associated with a common bclI restriction fragment length polymorphism (RFLP) of the GR gene (Panarelli et al., 1998), though…”

“11 -HSD1 is expressed in kidneys of rats but negligible expression occurs in adult human kidney (Stewart et al., 1994).”

“Moreover cortisone, unlike cortisol, shows no pronounced diurnal rhythm and so is constantly available for conversion to active glucocorticoid (Walker et al., 1992).”

“More plausibly, adipose tissue dissociation and culture lead to early induction of adipocyte cytokine synthesis and release (Ruan et al., 2003).”

“In terms of isozymes, 11 -HSD1, but not 11 -HSD2, mRNA is expressed in rat white (epididymal) adipose tissue (WAT) (Napolitano et al., 1998) and in human adipose tissue (Bujalska et al., 1997; Sun et al., 1997; Paulmyer-Lacroix et al., 2002).”

“Other central effects of increased glucocorticoid action include depression (Cohen, 1980), which intriguingly is also linked specifically to idiopathic visceral obesity (Ahlberg et al., 2002).”

“The discordance of reported reaction direction in intact cells, largely involving Leydig cells and preadipocytes (Bujalska et al., 2002), remains unresolved but is an important issue, given the current enthusiasm to decrease/inhibit 11-ketoreductase as a therapeutic target.”

“In humans with hypopituitarism and acromegaly, this effect may be important (Moore et al., 1999; Trainer et al., 2001; Tiosano et al., 2003).”

“In the 2 decades since excess cortisol production and clearance rates were first noted in obesity (Strain et al., 1980), the observation has been repeated many times (Andrew et al.”

“However, increased feedback sensitivity may not be applicable to obese men (Pasquali et al., 2002), although this sex is typified by a more-android adipose distribution!”

“…life, including the placenta (Brown et al., 1996a), in adults, 11 -HSD2 is expressed principally in tissues where aldosterone induces its classical effects on sodium excretion, including distal nephron, sweat glands, salivary glands, and colonic mucosa (Smith et al., 1996; Hirasawa et al., 1997).”

“…drive to the HPA axis — perhaps reflecting some form of primary meal-related abnormality of cortisol release — moderate chronic stress (Rosmond et al., 1998), and/or reduced sensitivity to HPA axis feedback have been suggested (Ljung et al., 1996; Di Blasio et al., 2003; Jessop et al., 2003).”

“Moreover, the feedback defect appears linked more to MR than GR, both in obese rodents (Mattsson et al., 2003) and humans (Jessop et al., 2003).”

“For the metabolic syndrome, case-control and cross-sectional studies have suggested that high blood pressure associates with somewhat elevated cortisol concentrations (in blood, saliva, or urine) (Watt et al., 1992; Filipovsky et al., 1996; Stolk et al., 1996; Rosmond et al., 1998; Walker et al., 1998; Fraser et al.,…”

“However, the phenotypes are complex, since GR in the CNS also play a key role in HPA axis control such that a generalised transgenic reduction of GR causes obesity (Pepin et al., 1989).”

“In contrast, adipose mRNA-encoding resistin, which may lead to insulin resistance (Steppan et al., 2001), is reduced in transgenic adipose tissue, perhaps as a consequence of glucocorticoid excess (Viengchareun et al., 2002).”

“…lipoprotein lipase — thereby liberating free fatty acids (FFAs) from peripheral fat — but, on the other hand, stimulate preadipocyte differentiation and enhance substrate flux in favour of gluconeogenesis and triglyceride synthesis in central fat (Samra et al., 1998; Andrews and Walker, 1999).”

“Indeed, GH therapy reduces cortisol:cortisone metabolite ratios in patients with hypopituitarism (Weaver et al., 1994) and in idiopathic obesity (Tomlinson et al.”

“In male rats, estradiol potently downregulates 11 -HSD1 expression (Low et al., 1993) and, only in the presence of glucocorticoids, downregulates PEPCK expression (P.M. Jamieson et al., 1999).”

“Nonetheless, 11 -HSD1 co-precipitates with the NADPH-generating enzyme, hexose-6-phosphate dehydrogenase (Ozols, 1995), which may dictate the predominant 11-ketoreductase action of 11 -HSD1 in vivo (Draper et al., 2003).”

“Moreover, dermal (vascular) sensitivity to GR agonists correlates with component disorders of the metabolic syndrome (Walker et al., 1996,1998; Andrews et al., 2002) and is associated with a common bclI restriction fragment length polymorphism (RFLP) of the GR gene (Panarelli et al., 1998), though…”

“In terms of more-direct effects, CCAAT/enhancer binding protein alpha (C/EBP ) binds to several sites on the 11 -HSD1 promoter and, when transfected into human hepatoma hepG2 cells, increases 11 -HSD1 promoter activity (Williams et al., 2000).”

“Liver X receptor (LXR) agonists also partially downregulate 11 -HSD1 in vitro and in vivo (Stulnig et al., 2002).”

“Other central effects of increased glucocorticoid action include depression (Cohen, 1980), which intriguingly is also linked specifically to idiopathic visceral obesity (Ahlberg et al., 2002).”

“In vivo, the main source of 11-ketosteroid is 11 -HSD2 dehydrogenation of cortisol and corticosterone, which predominantly occurs in the kidney (Whitworth et al., 1989).”

“…transfected with 11 -HSD1 cDNA or in primary cells in culture show that in most, if not all, intact cells and organs, this enzyme is a predominant 11- ketoreductase, reactivating inert cortisone into cortisol (Low et al., 1994a; Hundertmark et al., 1995; Jamieson et al., 1995; Rajan et al., 1996).”

“Isolated perfused cat (Bush et al., 1968) or rat (Jamieson et al.”

“, 2003), anterior pituitary gland, brain (including hippocampus) (Moisan et al., 1990a,b; Lakshmi et al., 1991; Sakai et al., 1992), and adrenal cortex (Shimojo et al.”

“Notably, these locations have high GR rather than MR expression, with the exception of hippocampus and heart, where MR act as high-affinity sites for physiological glucocorticoids rather than aldosterone in vivo (Whorwood et al., 1991).”

“, 2002), although this sex is typified by a more-android adipose distribution! Several studies suggest that individuals with common GR polymorphisms demonstrate HPA axis abnormalities in addition to a peripheral phenotype of increased adiposity, insulin resistance, and hypertension (Bjorntorp et al., 1999; Rosmond et…”

“PPAR ligands cause fat redistribution to the periphery, which may underpin the favourable morphology seen (Kelly et al., 1999; Sewter et al., 2002).”

“Inhibitors have provided some conflicting data that may relate to difficulties in access of carbenoxolone to adipose tissue in vivo, at least in the doses administered to rodent models (Livingstone and Walker, 2003) and perhaps humans (Andrews et al., 2003).”

“There is some expression in other epithelial cells, such as in lung (Page et al., 1994) and endothelium (Brem et al., 1998; Hadoke et al., 1998; Christy et al., 2003).”

“Isolated perfused cat (Bush et al., 1968) or rat (Jamieson et al., 2000) liver models suggest that 11 -HSD1, which is the only isozyme expressed in liver, is a predominant 11 -reductase with a high capacity for reactivating 11-ketosteroid substrate over a broad range of substrate concentrations.”

“…et al., 1998), lung (Hundertmark et al., 1993), skeletal muscle, cardiac and vascular smooth muscle (Walker et al., 1991; Brem et al., 1995; Christy et al., 2003), anterior pituitary gland, brain (including hippocampus) (Moisan et al., 1990a,b; Lakshmi et al., 1991; Sakai et al., 1992),…”

“This is further supported by evidence that HPA axis responsiveness to stimuli such as acute stress, CRH/AVP (Pasquali et al., 1999), adrenergic manipulations (Pasquali et al., 2000), hypoglycaemia, or a standard meal (Marin et al., 1992; Hautanen and Adlercreutz, 1993) is enhanced in idiopathic…”

“…life, including the placenta (Brown et al., 1996a), in adults, 11 -HSD2 is expressed principally in tissues where aldosterone induces its classical effects on sodium excretion, including distal nephron, sweat glands, salivary glands, and colonic mucosa (Smith et al., 1996; Hirasawa et al., 1997).”

“Additionally important in glucocorticoid-induced obesity is central stimulation of appetite (Udden et al., 2003), mediated by complex interactions between hypothalamic responses to glucocorticoids, their effects upon target appetite-controlling neurotransmitters such as neuropeptide Y (NPY), and both central and perip…”

“…to stimuli such as acute stress, CRH/AVP (Pasquali et al., 1999), adrenergic manipulations (Pasquali et al., 2000), hypoglycaemia, or a standard meal (Marin et al., 1992; Hautanen and Adlercreutz, 1993) is enhanced in idiopathic obesity, particularly visceral obesity (Pasquali et al., 2000).”

“In a few studies (e.g., in Leydig cells), 11 -dehydrogenase activity has been reported in apparently intact cell preparations (Gao et al., 1997; Ge and Hardy, 2000).”

“, 2002) and may be targeted by 11 -HSD inhibitors (Jellinck et al., 1993).”

“Attempts to link the 11 -HSD1 genotype with obesity have not been successful (Caramelli et al., 2001; Draper et al., 2002), although arguably the intermediate phenotypes (i.”

“A-ring reductases (5 - and - ) are activated in both animal (Livingstone et al., 2000a) and human obesity (Andrew et al., 1998,2002).”

“In humans with hypopituitarism and acromegaly, this effect may be important (Moore et al., 1999; Trainer et al., 2001; Tiosano et al., 2003).”

“Proinflammatory cytokines such as tumor necrosis factor alpha (TNF ) and interleukin-1 (IL1) increase and anti-inflammatory cytokines reduce 11 -HSD1 in adipose cells in vitro (Handoko et al., 2000; Friedberg et al., 2003).”

“, 2003), mediated by complex interactions between hypothalamic responses to glucocorticoids, their effects upon target appetite-controlling neurotransmitters such as neuropeptide Y (NPY), and both central and peripheral effects upon adipose-derived endocrine mediators such as leptin and gut hormones (Solano and Jacobs…”

“In humans with hypopituitarism and acromegaly, this effect may be important (Moore et al., 1999; Trainer et al., 2001; Tiosano et al., 2003).”

“…cortisol response to particular types of food may differ with the locus of adiposity, as viscerally obese women show lower HPA axis responses to high-fat and protein but greater responses to high-carbohydrate meals, compared to peripherally obese and lean subjects (Vicennati et al., 2002).”

“In male rats, estradiol potently downregulates 11 -HSD1 expression (Low et al., 1993) and, only in the presence of glucocorticoids, downregulates PEPCK expression (P.M. Jamieson et al., 1999).”

“…studies have suggested that high blood pressure associates with somewhat elevated cortisol concentrations (in blood, saliva, or urine) (Watt et al., 1992; Filipovsky et al., 1996; Stolk et al., 1996; Rosmond et al., 1998; Walker et al., 1998; Fraser et al., 1999; Brunner et al., 2002).”

“Intriguingly, while polymorphisms in the 11 -HSD1 gene (HSD11B1) correlate rather poorly (Draper et al., 2002; Gelernter-Yaniv et al., 2003), if at all (Caramelli et al., 2001), with adipose distribution in humans, changes in the hexose-6-phosphate dehydrogenase gene may be key.”

“This might be of pathogenic relevance in cases such as patients with the insulin resistance of myotonic dystrophy (Johansson et al., 2001), in which liver 11 -HSD1 activity is raised.”

“Importantly, in humans, GR mRNA levels in skeletal muscle correlate with insulin sensitivity and blood pressure (Reynolds et al., 2002; Whorwood et al., 2002).”

“Others have found predominantly 11-ketoreduction in similar preparations (Leckie et al., 1998).”

“…transfected with 11 -HSD1 cDNA or in primary cells in culture show that in most, if not all, intact cells and organs, this enzyme is a predominant 11- ketoreductase, reactivating inert cortisone into cortisol (Low et al., 1994a; Hundertmark et al., 1995; Jamieson et al., 1995; Rajan et al., 1996).”

“…et al., 1993), skeletal muscle, cardiac and vascular smooth muscle (Walker et al., 1991; Brem et al., 1995; Christy et al., 2003), anterior pituitary gland, brain (including hippocampus) (Moisan et al., 1990a,b; Lakshmi et al., 1991; Sakai et al., 1992), and adrenal cortex (Shimojo et al., 1996).”

“The preponderant reductive direction in vivo appears to be due more to the intracellular redox context of 11 -HSD1 in the inner leaflet of the endoplasmic reticulum than to any structural feature, such as glycosylation (Agarwal et al., 1995).”

“11 -HSD1 mRNA regulation in 3T3-F442A cells parallels glycerol-3-phosphate dehydrogenase, a key enzyme in triglyceride synthesis and a well-characterised marker of adipocyte differentiation (Moustaid et al., 1990).”

“Indeed, GH therapy reduces cortisol:cortisone metabolite ratios in patients with hypopituitarism (Weaver et al., 1994) and in idiopathic obesity (Tomlinson et al., 2003).”

“Additionally, 11 -HSD1 null animals show greater induction of uncoupling protein-2 (UCP-2) in mesenteric adipose tissue than WT mice (Morton et al., 2002), which may allow local calorie wastage rather than storage as fat (Digby et al., 2000).”

“C. 11 -HSD IN THE BRAIN IN OBESITY While not the main object of this review (for details of 11 -HSDs in the CNS, see Seckl, 1997; Yau and Seckl, 2001), specific CNS changes in 11 -HSDs in obese rodents have been reported that add to the complexity of tissue-specific dysregulation.”

“, 2002), although this sex is typified by a more-android adipose distribution! Several studies suggest that individuals with common GR polymorphisms demonstrate HPA axis abnormalities in addition to a peripheral phenotype of increased adiposity, insulin resistance, and hypertension (Bjorntorp et al., 1999; Rosmond et…”

“Attempts to link the 11 -HSD1 genotype with obesity have not been successful (Caramelli et al., 2001; Draper et al., 2002), although arguably the intermediate phenotypes (i.”

“…supported by evidence that HPA axis responsiveness to stimuli such as acute stress, CRH/AVP (Pasquali et al., 1999), adrenergic manipulations (Pasquali et al., 2000), hypoglycaemia, or a standard meal (Marin et al., 1992; Hautanen and Adlercreutz, 1993) is enhanced in idiopathic obesity,…”

“Studies in adipose cells derived from the mammary gland confirmed the presence of 11 -dehydrogenase activity in vitro (Quirk et al., 1991).”

“UCP-2 is downregulated by glucocorticoids (Udden et al., 2001) and upregulated by PPAR activation (Kelly et al.”

“, 1998), lung (Hundertmark et al., 1993), skeletal muscle, cardiac and vascular smooth muscle (Walker et al.”

“Increased tissue sensitivity to glucocorticoids has gained significant attention with the discovery of 11-β hydroxysteroid dehydrogenase (11β HSD), an enzyme that regulates glucocorticoid access to the receptors in peripheral and brain tissue and converts inactive glucocorticoids such as cortisone to active glucocorti…”

“individuals also exhibit increased cortisol clearance and production rates [40] with increased HPA axis activation [43].”

“Increased local 11b-HSD1 activity may contribute to dyslipidemia through glucocorticoid-enhanced lipolysis and decreased lipoprotein lipase (LPL) activity in peripheral, subcutaneous adipose tissue resulting in net increased free fatty acid release.(296) Increased 11b-HSD1 activity in visceral adipose tissue correlate…”

“2): Whereas GCs increase lipolysis by inducing hormone-sensitive lipase [171] and reduce lipoprotein lipase (LPL) activity in peripheral fat depots, they promote pre-adipocyte differentiation, pro-lipogenic pathway activity, and thereby cellular hypertrophy in central fat [172-174] as well as decreased”

“in intact cells and enhances glucocorticoid receptor activation.((80,81)) In contrast, 11b-HSD2 potently inactivates glucocorticoids.”

“The increase in hepatic gluconeogenesis is due to impaired suppression of adipose tissue lipolysis, which increases the delivery of free fatty acids to the liver [62].”

“11 -HSD1 catalyzes the intracellular regeneration of cortisol from inactive cortisone and has been shown to amplify the effects of cortisol in the liver and fat cells (Seckl, 2004).”

“Supporting the relevance of locally generated glucocorticoid in WAT, transgenic mice overexpressing 11 HSD1 in adipocytes faithfully reproduced the metabolic syndrome (67,68), whereas deficient mice were metabolically resistant to high-fat feeding (69).”

“Symptoms of the metabolic X syndrome (visceral obesity, hypertension, type 2 diabetes) have considerable overlap with Cushingoid features [129].”

“, 1990), and are involved in the synthesis of active glucocorticoids through the presence of the type 1 form of the enzyme 11β-hydroxysteroid dehydrogenase (Seckl et al., 2004), adipose tissue being an important site in humans of the regeneration of cortisol from cortisone.”

“Adipose tissue is a site of activation of glucocorticoids with the regeneration of cortisol from cortisone in humans, and this occurs through expression in adipocytes of the type 1 form of the enzyme 11β-hydroxysteroid dehydrogenase (155).”

“2 Fig. 2. Effects of GCs on the insulin receptor signaling pathways. GC indicates the processes inhibited by GC excess. IRS-1 = Insulin receptor substrate-1; PI3K = phosphatidylinositol-3-kinase; PKB = protein kinase B; GSK-3 = glycogen synthase kinase-3. F02 Effects of GC Excess in Adipose Tissue GCs plays a pivotal…”

“Additionally, neuronal cells have also been shown to have bidirectional activity (37).”

“The oxidoreductase, 11 hydroxysteroid dehydrogenase type 1, mediates the conversion of cortisone to cortisol in humans and 11-dehydrocorticosterone to corticosterone in mice (10).”

“…of 11b-hydroxysteroid dehydrogenase type-1 (11bHSD1), a ubiquitously expressed enzyme that primarily functions to convert inactive glucocorticoids, such as cortisone (humans) and 11-dehydrocorticosterone (rodents) into their active relatives cortisol and corticosterone (Seckl et al., 2004).”

“[88] showed that 11β-HSD 1 knockout mice were resistant to many of the metabolic aberrations that occurred within the liver and adipocytes due to stress and high-fat diet.”

“Although cortisol plasma concentrations were shown not to be consistently elevated in obese people (Seckl et al. 2004), there is accumulating evidence for increased endogenous adipose tissue-specific glucocorticoid reactivation in human obesity (Mariniello et al.”

“The majority of murine cholesterol is in the form of high-density lipoprotein (HDL), whilst in humans low-density lipoprotein predominates [130] .”

“With altered patterns of cortisol secretion and impaired feedback control, individuals prone to gain fat also often suffer from tiredness, poor sleep, and central obesity (44, 45), all of which tend to aggravate this condition.”

“Third, glucocorticoids suppress insulin-stimulated glucose uptake in adipocytes, which might contribute to the modulation of whole body glucose homeostasis and insulin sensitivity [23-25].”

“Two isozymes exist, 11β-HSD1 and 11β-HSD2, with predominantly opposite reaction directions i vivo, driven by intracellular location and availability of co-substrate (H witt et al., 2005; Seckl, 2004).”

“In addition, the typical predominance of visceral fat occurring in patients with CS contributes to the worsening of insulin resistance (74, 75).”

“However, in obesity/metabolic syndrome, expression and activity of 11 -HSD1 are strikingly upregulated in adipose tissue (3–13), increasing tissue glucocorticoid levels and possibly explaining the paradoxical similarity between common metabolic syndrome/obesity spectrum disorders and rare Cushing’s syndrome (14).”

“Peripheral tissue sensitivity to glucocorticoids, genetic and environmental variations in glucocorticoid receptor density in various tissues, along with increased 11 β HSD 1 activity have all been proposed to underlie the metabolic syndrome [ 50 ].”

“Intracellular glucocorticoid metabolism is regulated at a prereceptor level (1) by the activity of two isoforms of the 11b-hydrxysteroid dehydrogenase enzyme: 11b-Hydrxysteroid dehydrogenase type 1 (11b-HSD1) is a microsomal enzyme, which acts mainly as a NADP(H)dependent reductase converting inactive cortisone (E) to…”

“Unfortunately, HSD11B1 SNPs are not consistently associated with MetS, despite overexpression producing a classic MetS phenotype in mice [47, 48 ].”

“Two 11β-HSD isozymes have been identified, 11β-HSD1 and 11β-HSD2 [26,27].”

“In addition to regulation of fatty acids homeostasis, glucocorticoids induce obesity by central stimulation of appetite (Seckl et al., 2004).”

“have shown that peripheral conversion of glucocorticoids is altered [23,24], that adipose tissue cortisol has a slow turnover, and that it”

“We also observed a trend to a higher hepatic 11β-HSD1 expression in those patients who had diagnosis of hypertension, which could be explained by higher angiotensinogen production secondary to hepatic hypercortisolism, as was observed in the transgenic mice model with selective overexpression of 11β-HSD1 in liver [17,…”

“It has been well established that chronically elevated levels of plasma GCs can lead to the development of a number of harmful pathologies, including impaired insulin signaling, central adiposity, skeletal muscle atrophy, immune suppression, and type 2 diabetes mellitus (6, 16, 24, 33).”

“Furthermore, dysregulation of this enzyme has been correlated with obesity and type 2 diabetes (Rask et al., 2001; Lindsay et al., 2003; Westerbacka et al., 2003; Seckl et al., 2004; Valsamakis et al., 2004) and decreased 11β-HSD mRNA is seen in ulcerative colitis (Takahasi et al.”

“…that converts inactive circulating 11-keto steroids into active glucocorticoids, are elevated in adipose tissue in some obese individuals, suggesting that adipose tissue-related glucocorticoid excess may underlie the risk for hyperglycemia related to greater IAF mass (Seckl et al., 2004).”

“The influence of 11b-HSD1 in mice and its potential as a therapeutic target in human subjects has been extensively reviewed elsewhere (Seckl & Walker, 2001, 2004; Seckl et al. 2004; Tomlinson et al. 2004b).”

“Those conversions occur in different tissues including kidney, liver and adipose tissue [58].”

“…cortisone and 11-dehydrocorticosterone, it has recently become a target for the development of specific treatments of the metabolic syndrome, type II diabetes, obesity, and the dementia associated with aging in which excessive cortisol action has a role (15, 20, 105, 221, 321, 408, 441, 465).”

“It is important to note that the adipogenic effects of GCs are often seen in situations where insulin is also elevated [3,15,27], rather than in humans on dietary restriction [8] or in animal models exposed to exercise training, as is shown here (Table 2) and in our previous study [16].”

“Increased local cortisol synthesis in adipose tissue via conversion of inactive cortisone to active cortisol by the action of type 1, 11beta-hydroxysteroid dehydrogenase enzyme, is another well-recognized etiologic factor for abdominal obesity.(77,79) Chronic excess of glucocorticoids, such as that seen with overt CS,…”

“glucocorticoid production as a result of adrenal tumors or because of prolonged treatment with high pharmacologic doses [31].”