scholarly journals Characterisation of 11β-hydroxysteroid dehydrogenase 1 in human orbital adipose tissue: a comparison with subcutaneous and omental fat

2007 ◽  
Vol 192 (2) ◽  
pp. 279-288 ◽  
Author(s):  
Iwona J Bujalska ◽  
Omar M Durrani ◽  
Joseph Abbott ◽  
Claire U Onyimba ◽  
Pamela Khosla ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Inflammatory Disease ◽  
Reductase Activity ◽  
Primary Cultures ◽  
Hydroxysteroid Dehydrogenase ◽  
Maximum Diameter ◽  
Tissue Remodelling ◽  
Tissue Mass ◽  
Disease States ◽  
The Metabolic Syndrome

Glucocorticoids (GCs) have a profound effect on adipose biology increasing tissue mass causing central obesity. The pre-receptor regulation of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that activates cortisol from cortisone has been postulated as a fundamental mechanism underlying the metabolic syndrome mediating adipocyte hyperplasia and hypertrophy in the omental (OM) depot. Orbital adipose tissue (OF) is the site of intense inflammation and tissue remodelling in several orbital inflammatory disease states. In this study, we describe features of the GC metabolic pathways in normal human OF depot and compare it with subcutaneous (SC) and OM depots. Using an automated histological characterisation technique, OF adipocytes were found to be significantly smaller (parameters: area, maximum diameter and perimeter) than OM and SC adipocytes (P<0.001). Although immunohistochemical analyses demonstrated resident CD68+ cells in all three whole tissue adipose depots, OF CD68 mRNA and protein expression exceeded that of OM and SC (mRNA, P<0.05; protein, P<0.001). In addition, there was higher expression of glucocorticoid receptor (GR)α mRNA in the OF whole tissue depot (P<0.05). Conversely, 11β-HSD1 mRNA together with the markers of late adipocyte differentiation (FABP4 and G3PDH) were significantly lower in OF. Primary cultures of OF preadipocytes demonstrated predominant 11β-HSD1 oxo-reductase activity with minimal dehydrogenase activity. Orbital adipocytes are smaller, less differentiated, and express low levels of 11β-HSD1 but abundant GRα compared with SC and OM. OF harbours a large CD68+ population. These characteristics define an orbital microenvironment that has the potential to respond to sight-threatening orbital inflammatory disease.

scholarly journals A novel selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis

2008 ◽  
Vol 197 (2) ◽  
pp. 297-307 ◽  
Author(s):  
I J Bujalska ◽  
L L Gathercole ◽  
J W Tomlinson ◽  
C Darimont ◽  
J Ermolieff ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mrna Expression ◽  
Adipocyte Differentiation ◽  
Reductase Activity ◽  
Primary Cultures ◽  
Hydroxysteroid Dehydrogenase ◽  
Novel Therapy ◽  
Fatty Acid Binding ◽  
Glucose Output

Glucocorticoid excess increases fat mass, preferentially within omental depots; yet circulating cortisol concentrations are normal in most patients with metabolic syndrome (MS). At a pre-receptor level, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates cortisol from cortisone locally within adipose tissue, and inhibition of 11β-HSD1 in liver and adipose tissue has been proposed as a novel therapy to treat MS by reducing hepatic glucose output and adiposity. Using a transformed human subcutaneous preadipocyte cell line (Chub-S7) and human primary preadipocytes, we have defined the role of glucocorticoids and 11β-HSD1 in regulating adipose tissue differentiation. Human cells were differentiated with 1.0 μM cortisol (F), or cortisone (E) with or without 100 nM of a highly selective 11β-HSD1 inhibitor PF-877423. 11β-HSD1 mRNA expression increased across adipocyte differentiation (P<0.001, n=4), which was paralleled by an increase in 11β-HSD1 oxo-reductase activity (from nil on day 0 to 5.9±1.9 pmol/mg per h on day 16, P<0.01, n=7). Cortisone enhanced adipocyte differentiation; fatty acid-binding protein 4 expression increased 312-fold (P<0.001) and glycerol-3-phosphate dehydrogenase 47-fold (P<0.001) versus controls. This was abolished by co-incubation with PF-877423. In addition, cellular lipid content decreased significantly. These findings were confirmed in the primary cultures of human subcutaneous preadipocytes. The increase in 11β-HSD1 mRNA expression and activity is essential for the induction of human adipogenesis. Blocking adipogenesis with a novel and specific 11β-HSD1 inhibitor may represent a novel approach to treat obesity in patients with MS.

scholarly journals Modulation of 11β-Hydroxysteroid Dehydrogenase Isozymes by Growth Hormone and Insulin-Like Growth Factor: In Vivo and In Vitro Studies1

1999 ◽  
Vol 84 (11) ◽  
pp. 4172-4177 ◽  
Author(s):  
J. S. Moore ◽  
J. P. Monson ◽  
G. Kaltsas ◽  
P. Putignano ◽  
P. J. Wood ◽  
...  
Keyword(s):  
Growth Factor ◽  
Reductase Activity ◽  
Primary Cultures ◽  
Inverse Correlation ◽  
Hydroxysteroid Dehydrogenase ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Glucose Output

The interconversion of hormonally active cortisol (F) and inactive cortisone (E) is catalyzed by two isozymes of 11β-hydroxysteroid dehydrogenase (11βHSD), an oxo-reductase converting E to F (11βHSD1) and a dehydrogenase (11βHSD2) converting F to E. 11βHSD1 is important in mediating glucocorticoid-regulated glucose homeostasis and regional adipocyte differentiation. Earlier studies conducted with GH-deficient subjects treated with replacement GH suggested that GH may modulate 11βHSD1 activity. In 7 acromegalic subjects withdrawing from medical therapy (Sandostatin-LAR; 20–40 mg/month for at least 12 months), GH rose from 7.1 ± 1.5 to 17.5 ± 4.3 mU/L (mean ± se), and insulin-like growth factor I (IGF-I) rose from 43.0 ± 8.8 to 82.1 ± 13.7 nmol/L (both P &lt; 0.05) 4 months after treatment. There was a significant alteration in the normal set-point of F to E interconversion toward E. The fall in the urinary tetrahydrocortisols/tetrahydocortisone ratio (THF+allo-THF/THE; 0.82 ± 0.06 to 0.60 ± 0.06; P &lt; 0.02) but unaltered urinary free F/urinary free E ratio (a marker for 11βHSD2 activity) suggested that this was due to inhibition of 11βHSD1 activity. An inverse correlation between GH and the THF+allo-THF/THE ratio was observed (r = −0.422; P &lt; 0.05). Conversely, in 12 acromegalic patients treated by transsphenoidal surgery (GH falling from 124 ± 49.2 to 29.3 ± 15.4 mU/L; P &lt; 0.01), the THF+allo-THF/THE ratio rose from 0.53 ± 0.06 to 0.63 ± 0.07 (P &lt; 0.05). Patients from either group who failed to demonstrate a change in GH levels showed no change in the THF+allo-THF/THE ratio. In vitro studies conducted on cells stably transfected with either the human 11βHSD1 or 11βHSD2 complementary DNA and primary cultures of human omental adipose stromal cells expressing only the 11βHSD1 isozyme indicated a dose-dependent inhibition of 11βHSD1 oxo-reductase activity with IGF-I, but not GH. Neither IGF-I nor GH had any effect on 11βHSD2 activity. GH, through an IGF-I-mediated effect, inhibits 11βHSD1 activity. This reduction in E to F conversion will increase the MCR of F, and care should be taken to monitor the adequacy of function of the hypothalamo-pituitary-adrenal axis in acromegalic subjects and in GH-deficient, hypopituitary patients commencing replacement GH therapy. Conversely, enhanced E to F conversion occurs with a reduction in GH levels; in liver and adipose tissue this would result in increased hepatic glucose output and visceral adiposity, suggesting that part of the phenotype currently attributable to adult GH deficiency may be an indirect consequence of its effect on tissue F metabolism via 11βHSD1 expression.

scholarly journals Androgen generation in adipose tissue in women with simple obesity – a site-specific role for 17β-hydroxysteroid dehydrogenase type 5

2004 ◽  
Vol 183 (2) ◽  
pp. 331-342 ◽  
Author(s):  
Marcus Quinkler ◽  
Binayak Sinha ◽  
Jeremy W Tomlinson ◽  
Iwona J Bujalska ◽  
Paul M Stewart ◽  
...  
Keyword(s):  
Weight Loss ◽  
Adipose Tissue ◽  
Subcutaneous Fat ◽  
Human Adipose Tissue ◽  
Hydroxysteroid Dehydrogenase ◽  
Rt Pcr ◽  
Androgen Synthesis ◽  
The Metabolic Syndrome ◽  
Simple Obesity ◽  
Omental Fat

Women with polycystic ovary syndrome (PCOS) have high circulating androgens, thought to originate from ovaries and adrenals, and frequently suffer from the metabolic syndrome including obesity. However, serum androgens are positively associated with body mass index (BMI) not only in PCOS, but also in simple obesity, suggesting androgen synthesis within adipose tissue. Thus we investigated androgen generation in human adipose tissue, including expression of 17β-hydroxysteroid dehydrogenase (17β-HSD) isozymes, important regulators of sex steroid metabolism. Paired omental and subcutaneous fat biopsies were obtained from 27 healthy women undergoing elective abdominal surgery (age range 30–50 years; BMI 19.7–39.2 kg/m2). Enzymatic activity assays in preadipocyte proliferation cultures revealed effcient conversion of androstenedione to testosterone in both subcutaneous and omental fat. RT-PCR of whole fat and preadipocytes of subcutaneous and omental origin showed expression of 17β-HSD types 4 and 5, but no relevant expression of 17β-HSD types 1, 2, or 3. Microarray analysis confirmed this expression pattern (17β-HSD5>17β-HSD4) and suggested a higher expression of 17β-HSD5 in subcutaneous fat. Accordingly, quantitative real-time RT-PCR showed significantly higher expression of 17β-HSD5 in subcutaneous compared with omental fat (P<0.05). 17β-HSD5 expression in subcutaneous, but not omental, whole fat correlated significantly with BMI (r=0.51, P<0.05). In keeping with these findings, 17β-HSD5 expression in subcutaneous fat biopsies from six women taking part in a weight loss study decreased significantly with weight loss (P<0.05). A role for 17β-HSD5 in adipocyte differentiation was further supported by the observed increase in 17β-HSD5 expression upon differentiation of stromal preadipocytes to mature adipocytes (n=5; P<0.005), which again was higher in cells of subcutaneous origin. Functional activity of 17β-HSD5 also significantly increased with differentiation, revealing a net gain in androgen activation (androstenedione to testosterone) in subcutaneous cultures, contrasting with a net gain in androgen inactivation (testosterone to androstenedione) in omental cultures. Thus, human adipose tissue is capable of active androgen synthesis catalysed by 17β-HSD5, and increased expression in obesity may contribute to circulating androgen excess.

scholarly journals Increased 5α-Reductase Activity and Adrenocortical Drive in Women with Polycystic Ovary Syndrome

2009 ◽  
Vol 30 (5) ◽  
pp. 536-536
Author(s):  
Dimitra A. Vassiliadi ◽  
Thomas M. Barber ◽  
Beverly A. Hughes ◽  
Mark I. McCarthy ◽  
John A. H. Wass ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Reductase Activity ◽  
Tertiary Care ◽  
Hydroxysteroid Dehydrogenase ◽  
Cross Sectional Study ◽  
Ovary Syndrome ◽  
Cross Sectional ◽  
Cortisol Metabolism ◽  
The Metabolic Syndrome

ABSTRACT Context Polycystic Ovary Syndrome (PCOS) is characterized by hyperandrogenism, anovulation and susceptibility to the metabolic syndrome. Altered peripheral cortisol metabolism has been reported in PCOS but also in simple obesity. Objective To describe cortisol metabolism and metabolic characteristics of a large PCOS cohort and to delineate the effect of obesity by comparison to BMI-matched controls. Design Observational, cross-sectional study. Setting Outpatient clinics of two secondary/tertiary care centres Patients or Other Participants 178 PCOS patients fulfilling Rotterdam criteria and 100 BMI-matched controls. Intervention 24-h urine collection for steroid metabolite excretion, fasting blood samples followed by an OGTT. Main Outcome Measures Urinary steroid metabolites including glucocorticoids and androgens and the ratios reflecting enzymatic activities involved in peripheral cortisol and androgen metabolism, 5α-reductase and 11β-hydroxysteroid dehydrogenase type 1 and 2. Circulating levels of glucose, insulin, DHEA, DHEAS and testosterone, calculation of HOMA. Results Total androgen metabolites were higher in PCOS compared to BMI-matched controls (4105 ± 2047 vs. 2532 ± 1610 μg/24h for the non-obese, 5547 ± 2911 vs. 2468 ± 1794 μg/24hr for the obese, both p &lt; 0.001). Total glucocorticoid metabolites were higher in obese PCOS vs. controls (10786 ± 3852 vs. 8834 ± 4487 μg/24hr, p = 0.001). 5α-reductase activity correlated with BMI, insulin levels and HOMA. Both obese and non-obese PCOS patients had higher 5α-reductase activity than controls (all p &lt; 0.05). 11β-hydroxysteroid dehydrogenase activities did not differ between PCOS and controls. Conclusions PCOS is associated with enhanced androgen and cortisol metabolite excretion and increased 5α-reductase activity that cannot be explained by obesity alone. Increased adrenal corticosteroid production represents an important pathogenic pathway in PCOS.

scholarly journals Local Androgen Inactivation in Abdominal Visceral Adipose Tissue

2003 ◽  
Vol 88 (12) ◽  
pp. 5944-5950 ◽  
Author(s):  
Karine Blouin ◽  
Christian Richard ◽  
Chantal Bélanger ◽  
Pierre Dupont ◽  
Marleen Daris ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Time Course ◽  
Primary Cultures ◽  
Visceral Obesity ◽  
Maximum Velocity ◽  
Hydroxysteroid Dehydrogenase ◽  
Omental Adipose Tissue ◽  
Conversion Rates ◽  
Visceral Adipose

Abstract We examined the expression and activity of two enzymes from the aldoketoreductase (AKR) family 1C, namely type 5 17β-hydroxysteroid dehydrogenase (17β-HSD-5, AKR1C3) and type 3 3α-hydroxysteroid dehydrogenase (3α-HSD-3, AKR1C2) in female sc and omental adipose tissue and in preadipocyte primary cultures. 17β-HSD-5 preferentially synthesizes testosterone from the inactive adrenal precursor androstenedione, whereas 3α-HSD-3 inactivates dihydrotestosterone. mRNAs of both enzymes were detected in adipose tissue from the omental and sc compartments. Real-time PCR quantification indicated a 3-fold higher 3α-HSD-3 expression compared with 17β-HSD-5, and the expression of both enzymes tended to be higher in the sc vs. the omental depot. Accordingly, dose-response and time-course experiments performed in preadipocyte primary cultures indicated that 3α-HSD activity was higher than 17β-HSD activity (13-fold maximum velocity difference). We measured 3α-HSD activity in omental and sc adipose tissue samples of 32 women for whom body composition and body fat distribution were evaluated by dual-energy x-ray absorptiometry and CT, respectively. We found that androgen inactivation in omental adipose tissue through 3α-HSD activity was significantly higher in women with elevated vs. low visceral adipose tissue accumulation (1.7-fold difference; P &lt; 0.05). Moreover, omental adipose tissue 3α-HSD activity was positively and significantly associated with CT-measured visceral adipose tissue (r = 0.43; P &lt; 0.02) and omental adipocyte diameter (r = 0.42; P &lt; 0.02). These results indicate that local androgen inactivation is a predominant reaction in female abdominal adipose tissue, with the greatest conversion rates observed in the presence of abdominal visceral obesity. Increased androgen inactivation in omental adipose tissue of abdominally obese women may impact locally on the regulation of adipocyte metabolism.

The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome

2013 ◽  
Vol 15 (2) ◽  
Author(s):  
Roland H. Stimson ◽  
Brian R. Walker
Keyword(s):  
Metabolic Disease ◽  
Adipose Tissue ◽  
Selective Inhibition ◽  
Hydroxysteroid Dehydrogenase ◽  
The Metabolic Syndrome ◽  
Specific Regulation ◽  
Visceral Adipose ◽  
Subcutaneous Adipose

AbstractThe cortisol regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels, particularly in the liver and adipose tissue. The importance of this enzyme in causing metabolic disease was highlighted by transgenic mice which over- or under-expressed 11β-HSD1; consequently, selective 11β-HSD1 inhibitors have been widely developed as novel agents to treat obesity and type 2 diabetes mellitus (T2DM). This review focuses on the importance of 11β-HSD1 in humans which has been more difficult to ascertain. The recent development of a deuterated cortisol tracer has allowed us to quantify in vivo cortisol production by 11β-HSD1. These results have been surprising, as cortisol production rates by 11β-HSD1 are at least equivalent to that of the adrenal glands. The vast majority of this production is by the liver (>90%) with a smaller contribution from subcutaneous adipose tissue and possibly skeletal muscle, but with no detectable production from visceral adipose tissue. This tracer has also allowed us to quantify the tissue-specific regulation of 11β-HSD1 observed in obesity and obesity-associated T2DM, determine the likely basis for this dysregulation, and identify obese patients with T2DM as the group most likely to benefit from selective inhibition of 11β-HSD1. Some of these inhibitors have now reached Phase II clinical development, demonstrating efficacy in the treatment of T2DM. We review these results and discuss whether selective 11β-HSD1 inhibitors are likely to be an important new therapy for metabolic disease.

scholarly journals Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity?

2008 ◽  
Vol 100 (2) ◽  
pp. 227-235 ◽  
Author(s):  
Paul Trayhurn ◽  
Bohan Wang ◽  
I. Stuart Wood
Keyword(s):  
Adipose Tissue ◽  
Inflammatory Response ◽  
Marker Gene ◽  
Hypoxia Inducible Factor ◽  
Subsequent Development ◽  
Obese Mouse ◽  
Human Adipocytes ◽  
Tissue Mass ◽  
Monocyte Chemoattractant Protein 1 ◽  
The Metabolic Syndrome

White adipose tissue is a key endocrine and secretory organ, releasing multiple adipokines, many of which are linked to inflammation and immunity. During the expansion of adipose tissue mass in obesity there is a major inflammatory response in the tissue with increased expression and release of inflammation-related adipokines, including IL-6, leptin, monocyte chemoattractant protein-1 and TNF-α, together with decreased adiponectin production. We proposed in 2004 (Trayhurn & Wood, Br J Nutr92, 347–355) that inflammation in adipose tissue in obesity is a response to hypoxia in enlarged adipocytes distant from the vasculature. Hypoxia has now been directly demonstrated in adipose tissue of several obese mouse models (ob/ob, KKAy, diet-induced) and molecular studies indicate that the level of the hypoxia-inducible transcription factor, hypoxia-inducible factor-1α, is increased, as is expression of the hypoxia-sensitive marker gene, GLUT1. Cell- culture studies on murine and human adipocytes show that hypoxia (induced by low O2 or chemically) leads to stimulation of the expression and secretion of a number of inflammation-related adipokines, including angiopoietin-like protein 4, IL-6, leptin, macrophage migration inhibitory factor and vascular endothelial growth factor. Hypoxia also stimulates the inflammatory response of macrophages and inhibits adipocyte differentiation from preadipocytes. GLUT1 gene expression, protein level and glucose transport by human adipocytes are markedly increased by hypoxia, indicating that low O2 tension stimulates glucose utilisation. It is suggested that hypoxia has a pervasive effect on adipocyte metabolism and on overall adipose tissue function, underpinning the inflammatory response in the tissue in obesity and the subsequent development of obesity-associated diseases, particularly type 2 diabetes and the metabolic syndrome.

scholarly journals Cellular hypoxia and adipose tissue dysfunction in obesity

2009 ◽  
Vol 68 (4) ◽  
pp. 370-377 ◽  
Author(s):  
I. Stuart Wood ◽  
Fátima Pérez de Heredia ◽  
Bohan Wang ◽  
Paul Trayhurn
Keyword(s):  
Adipose Tissue ◽  
Inflammatory Responses ◽  
Strong Support ◽  
Low Grade ◽  
Tissue Mass ◽  
Diverse Range ◽  
Monocyte Chemoattractant Protein 1 ◽  
The Metabolic Syndrome ◽  
Adipose Tissue Dysfunction ◽  
Cellular Hypoxia

Expansion of adipose tissue mass, the distinctive feature of obesity, is associated with low-grade inflammation. White adipose tissue secretes a diverse range of adipokines, a number of which are inflammatory mediators (such as TNFα, IL-1β, IL-6, monocyte chemoattractant protein 1). The production of inflammatory adipokines is increased with obesity and these adipokines have been implicated in the development of insulin resistance and the metabolic syndrome. However, the basis for the link between increased adiposity and inflammation is unclear. It has been proposed previously that hypoxia may occur in areas within adipose tissue in obesity as a result of adipocyte hypertrophy compromising effective O2 supply from the vasculature, thereby instigating an inflammatory response through recruitment of the transcription factor, hypoxic inducible factor-1. Studies in animal models (mutant mice, diet-induced obesity) and cell-culture systems (mouse and human adipocytes) have provided strong support for a role for hypoxia in modulating the production of several inflammation-related adipokines, including increased IL-6, leptin and macrophage migratory inhibition factor production together with reduced adiponectin synthesis. Increased glucose transport into adipocytes is also observed with low O2 tension, largely as a result of the up-regulation of GLUT-1 expression, indicating changes in cellular glucose metabolism. Hypoxia also induces inflammatory responses in macrophages and inhibits the differentiation of preadipocytes (while inducing the expression of leptin). Collectively, there is strong evidence to suggest that cellular hypoxia may be a key factor in adipocyte physiology and the underlying cause of adipose tissue dysfunction contributing to the adverse metabolic milieu associated with obesity.

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