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Marcus Quinkler Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom

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Binayak Sinha Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom

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Jeremy W Tomlinson Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom

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Iwona J Bujalska Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom

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Paul M Stewart Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom

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Wiebke Arlt Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom

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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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Iwona J Bujalska Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Omar M Durrani Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Joseph Abbott Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Claire U Onyimba Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Pamela Khosla Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Areeb H Moosavi Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Tristan T Q Reuser Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Paul M Stewart Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Jeremy W Tomlinson Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Elizabeth A Walker Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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Saaeha Rauz Department of Endocrinology, Division of Medical Sciences,
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham,
Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK

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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.

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Laura L Gathercole Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK

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Nikolaos Nikolaou Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Shelley E Harris Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Anastasia Arvaniti Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK

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Toryn M Poolman Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Jonathan M Hazlehurst Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK

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Denise V Kratschmar Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland

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Marijana Todorčević Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Ahmad Moolla Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Niall Dempster Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Ryan C Pink Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK

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Michael F Saikali Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

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Liz Bentley Mammalian Genetics Unit, Medical Research Council Harwell, Oxford, UK

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Trevor M Penning Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology & Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

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Claes Ohlsson Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Carolyn L Cummins Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

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Matti Poutanen Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland

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Alex Odermatt Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland

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Roger D Cox Mammalian Genetics Unit, Medical Research Council Harwell, Oxford, UK

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Jeremy W Tomlinson Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Steroid 5β-reductase (AKR1D1) plays important role in hepatic bile acid synthesis and glucocorticoid clearance. Bile acids and glucocorticoids are potent metabolic regulators, but whether AKR1D1 controls metabolic phenotype in vivo is unknown. Akr1d1–/– mice were generated on a C57BL/6 background. Liquid chromatography/mass spectrometry, metabolomic and transcriptomic approaches were used to determine effects on glucocorticoid and bile acid homeostasis. Metabolic phenotypes including body weight and composition, lipid homeostasis, glucose tolerance and insulin tolerance were evaluated. Molecular changes were assessed by RNA-Seq and Western blotting. Male Akr1d1–/– mice were challenged with a high fat diet (60% kcal from fat) for 20 weeks. Akr1d1–/– mice had a sex-specific metabolic phenotype. At 30 weeks of age, male, but not female, Akr1d1–/– mice were more insulin tolerant and had reduced lipid accumulation in the liver and adipose tissue yet had hypertriglyceridemia and increased intramuscular triacylglycerol. This phenotype was associated with sexually dimorphic changes in bile acid metabolism and composition but without overt effects on circulating glucocorticoid levels or glucocorticoid-regulated gene expression in the liver. Male Akr1d1–/– mice were not protected against diet-induced obesity and insulin resistance. In conclusion, this study shows that AKR1D1 controls bile acid homeostasis in vivo and that altering its activity can affect insulin tolerance and lipid homeostasis in a sex-dependent manner.

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Nikolaos Nikolaou Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Anastasia Arvaniti Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK

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Nathan Appanna Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Anna Sharp Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Beverly A Hughes Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, UK

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Dena Digweed Diurnal Ltd, Cardiff, UK

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Martin J Whitaker Diurnal Ltd, Cardiff, UK

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Richard Ross Department of Oncology and Metabolism, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, UK

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Wiebke Arlt Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, UK
NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK

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Trevor M Penning Department of Systems Pharmacology & Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

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Karen Morris Biochemistry Department, Manchester University NHS Trust, Manchester, UK

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Sherly George Biochemistry Department, Manchester University NHS Trust, Manchester, UK

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Brian G Keevil Biochemistry Department, Manchester University NHS Trust, Manchester, UK

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Leanne Hodson Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Laura L Gathercole Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK

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Jeremy W Tomlinson Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates endogenous glucocorticoids and catalyses an important step in bile acid synthesis. Endogenous and synthetic glucocorticoids are potent regulators of metabolic phenotype and play a crucial role in hepatic glucose metabolism. However, the potential of synthetic glucocorticoids to be metabolised by AKR1D1 as well as to regulate its expression and activity has not been investigated. The impact of glucocorticoids on AKR1D1 activity was assessed in human liver HepG2 and Huh7 cells; AKR1D1 expression was assessed by qPCR and Western blotting. Genetic manipulation of AKR1D1 expression was conducted in HepG2 and Huh7 cells and metabolic assessments were made using qPCR. Urinary steroid metabolite profiling in healthy volunteers was performed pre- and post-dexamethasone treatment, using gas chromatography-mass spectrometry. AKR1D1 metabolised endogenous cortisol, but cleared prednisolone and dexamethasone less efficiently. In vitro and in vivo, dexamethasone decreased AKR1D1 expression and activity, further limiting glucocorticoid clearance and augmenting action. Dexamethasone enhanced gluconeogenic and glycogen synthesis gene expression in liver cell models and these changes were mirrored by genetic knockdown of AKR1D1 expression. The effects of AKR1D1 knockdown were mediated through multiple nuclear hormone receptors, including the glucocorticoid, pregnane X and farnesoid X receptors. Glucocorticoids down-regulate AKR1D1 expression and activity and thereby reduce glucocorticoid clearance. In addition, AKR1D1 down-regulation alters the activation of multiple nuclear hormone receptors to drive changes in gluconeogenic and glycogen synthesis gene expression profiles, which may exacerbate the adverse impact of exogenous glucocorticoids.

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