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

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.

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Glucocorticoid-induced androgen inactivation by aldo-keto reductase 1C2 promotes adipogenesis in human preadipocytes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00069.2011 ◽

2012 ◽

Vol 302 (8) ◽

pp. E941-E949 ◽

Cited By ~ 23

Author(s):

Alain Veilleux ◽

Julie-Anne Côté ◽

Karine Blouin ◽

Mélanie Nadeau ◽

Mélissa Pelletier ◽

...

Keyword(s):

Adipose Tissue ◽

Lipid Accumulation ◽

Tissue Sample ◽

Subcutaneous Fat ◽

Human Adipose Tissue ◽

Preadipocyte Differentiation ◽

Omental Adipose Tissue ◽

Human Preadipocytes ◽

Omental Fat ◽

G3pdh Activity

Adipogenesis and lipid storage in human adipose tissue are inhibited by androgens such as DHT. Inactivation of DHT to 3α-diol is stimulated by glucocorticoids in human preadipocytes. We sought to characterize glucocorticoid-induced androgen inactivation in human preadipocytes and to establish its role in the antiadipogenic action of DHT. Subcutaneous and omental primary preadipocyte cultures were established from fat samples obtained in subjects undergoing abdominal surgeries. Inactivation of DHT to 3α/β-diol for 24 h was measured in dexamethasone- or vehicle-treated cells. Specific downregulation of aldo-keto reductase 1C (AKR1C) enzymes in human preadipocytes was achieved using RNA interference. In whole adipose tissue sample, cortisol production was positively correlated with androgen inactivation in both subcutaneous and omental adipose tissue ( P < 0.05). Maximal dexamethasone (1 μM) stimulation of DHT inactivation was higher in omental compared with subcutaneous fat from men as well as subcutaneous and omental fat from women ( P < 0.05). A significant positive correlation was observed between BMI and maximal dexamethasone-induced DHT inactivation rates in subcutaneous and omental adipose tissue of men and women ( r = 0.24, n = 26, P < 0.01). siRNA-induced downregulation of AKR1C2, but not AKR1C1 or AKR1C3, significantly reduced basal and glucocorticoid-induced androgen inactivation rates ( P < 0.05). The inhibitory action of DHT on preadipocyte differentiation was potentiated following AKR1C2 but not AKR1C1 or AKR1C3 downregulation. Specifically, lipid accumulation, G3PDH activity, and FABP4 mRNA expression in differentiated preadipocytes exposed to DHT were reduced further upon AKR1C2 siRNA transfection. We conclude that glucocorticoid-induced androgen inactivation is mediated by AKR1C2 and is particularly effective in omental preadipocytes of obese men. The interplay between glucocorticoids and AKR1C2-dependent androgen inactivation may locally modulate adipogenesis and lipid accumulation in a depot-specific manner.

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The Effect of Weight Loss on Serum Mannose-Binding Lectin Levels

Clinical and Developmental Immunology ◽

10.1155/2012/354894 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

P. H. Høyem ◽

J. M. Bruun ◽

S. B. Pedersen ◽

S. Thiel ◽

B. Richelsen ◽

...

Keyword(s):

Weight Loss ◽

Adipose Tissue ◽

Real Time ◽

Liver Tissue ◽

Human Adipose Tissue ◽

Mannose Binding Lectin ◽

Mrna Levels ◽

Rt Pcr ◽

Mannose Binding ◽

Binding Lectin

Background. Serum levels of the mannose-binding lectin (MBL), which is an activator of the complement system, have been considered as a pathogenic factor in a broad range of diseases, and means of modulating MBL are therefore being evaluated. In this study we examine the effects of weight loss on MBL levels, and in continuation of this if MBL is synthesized in human adipose tissue.Methods. 36 nondiabetic obese subjects received a very low-calorie diet (VLCD) of 800 kcal/day for 8 weeks. Blood samples were collected at baseline and after VLCD. Furthermore, we measured MBL mRNA levels by the real-time RT-PCR on human adipose tissue compared to liver tissue.Results. The mean body weight was reduced from106.3±2.6 kg to92.8±2.4 kg,P<0.0001. Median MBL at baseline was 746 μg/L (IQR 316–1190) versus 892 μg/L (IQR 336–1511) after 8 weeks,P=0.23. No correlations were found between weight loss and changes in MBL (r=-0.098,P=0.57). MBL real-time RT-PCR showed no expression of mRNA in adipose tissue, but as expected a good expression in liver tissue was seen.Conclusions. MBL levels are not affected by weight loss and MBL is not synthesized in human adipose tissue.

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Weight Loss Increases 11β-Hydroxysteroid Dehydrogenase Type 1 Expression in Human Adipose Tissue

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-031376 ◽

2004 ◽

Vol 89 (6) ◽

pp. 2711-2716 ◽

Cited By ~ 60

Author(s):

Jeremy W. Tomlinson ◽

Jasbir S. Moore ◽

Penny M. S. Clark ◽

Geoff Holder ◽

Lynette Shakespeare ◽

...

Keyword(s):

Weight Loss ◽

Adipose Tissue ◽

Human Adipose Tissue ◽

Hydroxysteroid Dehydrogenase

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Adipose tissue expression of 11beta-Hydroxysteroid dehydrogenase type 1 in cushing's syndrome and in obesity

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302007000800027 ◽

2007 ◽

Vol 51 (8) ◽

pp. 1397-1403 ◽

Cited By ~ 14

Author(s):

Daniela Espíndola-Antunes ◽

Claudio E. Kater

Keyword(s):

Adipose Tissue ◽

Cushing’S Syndrome ◽

Human Adipose Tissue ◽

Hydroxysteroid Dehydrogenase ◽

Cushing's Syndrome ◽

Intact Cells ◽

Fat Depots ◽

Cortisol Metabolism ◽

The Metabolic Syndrome

Glucocorticoids have a major role in determining adipose tissue metabolism and distribution. 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is a NADPH-dependent enzyme highly expressed in the liver and adipose tissue. In most intact cells and tissues it functions as a reductase (to convert inactive cortisone to active cortisol). It has been hypothesized that tissue-specific deregulation of cortisol metabolism may be involved in the complex pathophysiology of the metabolic syndrome (MS) and obesity. Transgenic mice overexpressing 11betaHSD1 in adipose tissue develop obesity with all features of the MS, whereas 11betaHSD1-knockout mice are protected from both. The bulk of evidences points to an overexpression and increased activity of 11betaHSD1 also in human adipose tissue. However, 11betaHSD1 seems to adjust local cortisol concentrations independently of its plasma levels. In Cushing's syndrome, 11betaHSD1 is downregulated and may not be responsible for the abdominal fat depots; it also undergoes downregulation in response to weight loss in human obesity. The nonselective 11betaHSD1 inhibitor carbenoxolone improves insulin sensitivity in humans, and selective inhibitors enhance insulin action in diabetic mice liver, thereby lowering blood glucose. Thus, 11betaHSD1 is now emerging as a modulator of energy partitioning and a promising pharmacological target to treat the MS and diabetes.

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Influence of Free Fatty Acid Concentrations and Weight Loss on Adipose Tissue Direct Free Fatty Acid Storage Rates

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab501 ◽

2021 ◽

Author(s):

Qingyi Jia ◽

B Gisella Carranza Leon ◽

Michael D Jensen

Keyword(s):

Weight Loss ◽

Adipose Tissue ◽

Fatty Acid ◽

Free Fatty Acid ◽

Subcutaneous Fat ◽

Premenopausal Women ◽

Tissue Level ◽

Research Unit ◽

Lower Body ◽

Plasma Ffa

Abstract Context The factors that determine the recycling of free fatty acids (FFA) back into different adipose tissue depots via the direct storage pathway are not completely understood. Objective To assess the interactions between adipocyte factors and plasma FFA concentrations that determine regional FFA storage rates. Design We measured direct adipose tissue FFA storage rates before and after weight loss under high FFA (intravenous somatostatin and epinephrine) and low (intravenous insulin and glucose) FFA concentrations. Setting Mayo Clinic Clinical Research Unit. Patients Sixteen premenopausal women, BMI 30 - 37 kg/m 2. Intervention Comprehensive lifestyle weight loss program. Main Outcome Measure Direct FFA storage rates in upper and lower body subcutaneous fat. Results Over the entire range of FFA and under isolated conditions of elevated FFA concentrations the storage rates of FFA into upper and lower body subcutaneous fat per unit lipid were associated with concentrations, not adipocyte fatty acid storage factors. Under low FFA conditions, direct FFA storage rates were related to adipocyte CD36 content, not tissue level content of fatty acid storage factors. Weight loss did not change these relationships. Conclusions The regulation of direct FFA storage under low FFA concentration conditions appears to be at the level of the cell/adipocyte content of CD36, whereas under high FFA concentration conditions direct FFA storage at the tissue level is predicted by plasma FFA concentrations, independent of adipocyte size or fatty acid storage factors. These observations offer novel insights into how adipose tissue regulates direct FFA storage in humans.

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Dynamics of adipose tissue changes measured by MRI in obese patients during Reduxin treatment

Obesity and metabolism ◽

10.14341/2071-8713-5128 ◽

2012 ◽

Vol 9 (4) ◽

pp. 39-43 ◽

Cited By ~ 2

Author(s):

T I Romantsova ◽

I V Poluboyarinova ◽

O V Roik

Keyword(s):

Weight Loss ◽

Adipose Tissue ◽

Waist Circumference ◽

Dynamic Assessment ◽

Randomized Study ◽

Subcutaneous Fat ◽

Obese Patients ◽

Anthropometric Parameters ◽

Imaging Results ◽

Clinically Significant

Objective. To study the influence of the drug Reduxine in obese patients on the distribution of adipose tissue measured by MRI. Methods. In an open, prospective, non-randomized study duration of 20 weeks included 31 obese patients aged 20 to 65 years. During the study, the anthropometric parameters and the dynamics of the area of adipose tissue by means of MR imaging. Results. Weight loss in patients averaged 9.0 kg. Clinically significant weight loss reached 23 people (79%). Median reduction in waist circumference was 10 cm. Dynamic assessment of adipose tissue by MRI was performed in 17 patients. Reduxine treatment induced statistically significant decrease of both visceral and subcutaneous fat. Conclusions. According to the results of MRI, the reduction in waist circumference in patients receiving Reduxine occurred by reducing the number of both subcutaneous and visceral fat in the abdominal area.

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Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Activity in Vivo Limits Glucocorticoid Exposure to Human Adipose Tissue and Decreases Lipolysis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-2325 ◽

2007 ◽

Vol 92 (3) ◽

pp. 857-864 ◽

Cited By ~ 71

Author(s):

Jeremy W. Tomlinson ◽

Mark Sherlock ◽

Beverley Hughes ◽

Susan V. Hughes ◽

Fiona Kilvington ◽

...

Keyword(s):

Adipose Tissue ◽

Single Dose ◽

Interstitial Fluid ◽

Human Adipose Tissue ◽

Serum Cortisol ◽

Hydroxysteroid Dehydrogenase ◽

Continuous Treatment ◽

Gas Chromatography Mass Spectrometry ◽

Glycerol Release

Abstract Context: The pathophysiological importance of glucocorticoids (GCs) is exemplified by patients with Cushing’s syndrome who develop hypertension, obesity, and insulin resistance. At a cellular level, availability of GCs to the glucocorticoid and mineralocorticoid receptors is controlled by the isoforms of 11β-hydroxysteroid dehydrogenase (11β-HSD). In liver and adipose tissue, 11β-HSD1 converts endogenous, inactive cortisone to active cortisol but also catalyzes the bioactivation of the synthetic prednisone to prednisolone. Objective: The objective of the study was to compare markers of 11β-HSD1 activity and demonstrate that inhibition of 11β-HSD1 activity limits glucocorticoid availability to adipose tissue. Design and Setting: This was a clinical study. Patients: Seven healthy male volunteers participated in the study. Intervention: Intervention included carbenoxolone (CBX) single dose (100 mg) and 72 hr of continuous treatment (300 mg/d). Main Outcome Measures: Inhibition of 11β-HSD1 was monitored using five different mechanistic biomarkers (serum cortisol and prednisolone generation, urinary corticosteroid metabolite analysis by gas chromatography/mass spectrometry, and adipose tissue microdialysis examining cortisol generation and glucocorticoid-mediated glycerol release). Results: Each biomarker demonstrated reduced 11β-HSD1 activity after CBX administration. After both a single dose and 72 hr of treatment with CBX, cortisol and prednisolone generation decreased as did the urinary tetrahydrocortisol+5α-tetrahydrocortisol to tetrahydrocortisone ratio. Using adipose tissue microdialysis, we observed decreased interstitial fluid cortisol availability with CBX treatment. Furthermore, a functional consequence of 11β-HSD1 inhibition was observed, namely decreased prednisone-induced glycerol release into adipose tissue interstitial fluid indicative of inhibition of GC-mediated lipolysis. Conclusion: CBX is able to inhibit rapidly the generation of active GC in human adipose tissue. Importantly, limiting GC availability in vivo has functional consequences including decreased glycerol release.

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