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Colin Farquharson Roslin Institute, University of Edinburgh, Midlothian, Edinburgh, UK

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Ruth Andrew University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK

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Mark Nixon Endocrinology, Queen's Medical Research Institute, University/British Heart Foundation Centre for Cardiovascular Science, Edinburgh EH16 4TJ, UK

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Rita Upreti Endocrinology, Queen's Medical Research Institute, University/British Heart Foundation Centre for Cardiovascular Science, Edinburgh EH16 4TJ, UK

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Ruth Andrew Endocrinology, Queen's Medical Research Institute, University/British Heart Foundation Centre for Cardiovascular Science, Edinburgh EH16 4TJ, UK

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5α-Reduced glucocorticoids (GCs) are formed when one of the two isozymes of 5α-reductase reduces the Δ4–5 double bond in the A-ring of GCs. These steroids are largely viewed inert, despite the acceptance that other 5α-dihydro steroids, e.g. 5α-dihydrotestosterone, retain or have increased activity at their cognate receptors. However, recent findings suggest that 5α-reduced metabolites of corticosterone have dissociated actions on GC receptors (GRs) in vivo and in vitro and are thus potential candidates for safer anti-inflammatory steroids. 5α-Dihydro- and 5α-tetrahydro-corticosterone can bind with GRs, but interest in these compounds had been limited, since they only weakly activated metabolic gene transcription. However, a greater understanding of the signalling mechanisms has revealed that transactivation represents only one mode of signalling via the GR and recently the abilities of 5α-reduced GCs to suppress inflammation have been demonstrated in vitro and in vivo. Thus, the balance of parent GC and its 5α-reduced metabolite may critically affect the profile of GR signalling. 5α-Reduction of GCs is up-regulated in liver in metabolic disease and may represent a pathway that protects from both GC-induced fuel dyshomeostasis and concomitant inflammatory insult. Therefore, 5α-reduced steroids provide hope for drug development, but may also act as biomarkers of the inflammatory status of the liver in metabolic disease. With these proposals in mind, careful attention must be paid to the possible adverse metabolic effects of 5α-reductase inhibitors, drugs that are commonly administered long term for the treatment of benign prostatic hyperplasia.

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Dawn E W Livingstone Endocrinology Unit, Queen's Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, 47, Little France Crescent, Edinburgh EH16 4TJ, UK

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Sarah L Grassick Endocrinology Unit, Queen's Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, 47, Little France Crescent, Edinburgh EH16 4TJ, UK

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Gillian L Currie Endocrinology Unit, Queen's Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, 47, Little France Crescent, Edinburgh EH16 4TJ, UK

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Brian R Walker Endocrinology Unit, Queen's Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, 47, Little France Crescent, Edinburgh EH16 4TJ, UK

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Ruth Andrew Endocrinology Unit, Queen's Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, 47, Little France Crescent, Edinburgh EH16 4TJ, UK

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In obese humans, metabolism of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and A-ring reduction (by 5α- and 5β-reductases) is dysregulated in a tissue specific manner. These changes have been recapitulated in leptin resistant obese Zucker rats but were not observed in high-fat fed Wistar rats. Recent data from mouse models suggest that such discrepancies may reflect differences in leptin signalling. We therefore compared glucocorticoid metabolism in murine models of leptin deficiency and resistance. Male ob/ob and db/db mice and their respective littermate controls (n=10–12/group) were studied at the age of 12 weeks. Enzyme activities and mRNA expression were quantified in snap-frozen tissues. The patterns of altered pathways of steroid metabolism in obesity were similar in ob/ob and db/db mice. In liver, 5β-reductase activity and mRNA were increased and 11β-HSD1 decreased in obese mice, whereas 5α-reductase 1 (5αR1) mRNA was not altered. In visceral adipose depots, 5β-reductase was not expressed, 11β-HSD1 activity was increased and 5αR1 mRNA was not altered in obesity. By contrast, in subcutaneous adipose tissue 11β-HSD1 and 5αR1 mRNA were decreased. Systematic differences were not found between ob/ob and db/db murine models of obesity, suggesting that variations in leptin signalling through the short splice variant of the Ob receptor do not contribute to dysregulation of glucocorticoid metabolism.

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Dawn E W Livingstone University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK
Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK

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Emma M Di Rollo University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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Tracy C-S Mak University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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Karen Sooy University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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Brian R Walker University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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Ruth Andrew University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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5α-Reductases irreversibly catalyse A-ring reduction of pregnene steroids, including glucocorticoids and androgens. Genetic disruption of 5α-reductase 1 in male mice impairs glucocorticoid clearance and predisposes to glucose intolerance and hepatic steatosis upon metabolic challenge. However, it is unclear whether this is driven by changes in androgen and/or glucocorticoid action. Female mice with transgenic disruption of 5α-reductase 1 (5αR1-KO) were studied, representing a ‘low androgen’ state. Glucocorticoid clearance and stress responses were studied in mice aged 6 months. Metabolism was assessed in mice on normal chow (aged 6 and 12 m) and also in a separate cohort following 1-month high-fat diet (aged 3 m). Female 5αR1-KO mice had adrenal suppression (44% lower AUC corticosterone after stress), and upon corticosterone infusion, accumulated hepatic glucocorticoids (~27% increased corticosterone). Female 5αR1-KO mice aged 6 m fed normal chow demonstrated insulin resistance (~35% increased area under curve (AUC) for insulin upon glucose tolerance testing) and hepatic steatosis (~33% increased hepatic triglycerides) compared with controls. This progressed to obesity (~12% increased body weight) and sustained insulin resistance (~38% increased AUC insulin) by age 12 m. Hepatic transcript profiles supported impaired lipid β-oxidation and increased triglyceride storage. Female 5αR1-KO mice were also predisposed to develop high-fat diet-induced insulin resistance. Exaggerated predisposition to metabolic disorders in female mice, compared with that seen in male mice, after disruption of 5αR1 suggests phenotypic changes may be underpinned by altered metabolism of glucocorticoids rather than androgens.

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Dawn E W Livingstone Endocrinology, Queen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

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Emma M Di Rollo Endocrinology, Queen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

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Chenjing Yang Endocrinology, Queen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

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Lucy E Codrington Endocrinology, Queen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

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John A Mathews Endocrinology, Queen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

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Madina Kara Endocrinology, Queen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

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Katherine A Hughes Endocrinology, Queen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

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Christopher J Kenyon Endocrinology, Queen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

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Brian R Walker Endocrinology, Queen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

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Ruth Andrew Endocrinology, Queen's Medical Research Institute, University and British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

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Patients with critical illness or hepatic failure exhibit impaired cortisol responses to ACTH, a phenomenon known as ‘relative adrenal insufficiency’. A putative mechanism is that elevated bile acids inhibit inactivation of cortisol in liver by 5α-reductases type 1 and type 2 and 5β-reductase, resulting in compensatory downregulation of the hypothalamic–pituitary–adrenal axis and adrenocortical atrophy. To test the hypothesis that impaired glucocorticoid clearance can cause relative adrenal insufficiency, we investigated the consequences of 5α-reductase type 1 deficiency in mice. In adrenalectomised male mice with targeted disruption of 5α-reductase type 1, clearance of corticosterone was lower after acute or chronic (eightfold, P<0.05) administration, compared with WT control mice. In intact 5α-reductase-deficient male mice, although resting plasma corticosterone levels were maintained, corticosterone responses were impaired after ACTH administration (26% lower, P<0.05), handling stress (2.5-fold lower, P<0.05) and restraint stress (43% lower, P<0.05) compared with WT mice. mRNA levels of Nr3c1 (glucocorticoid receptor), Crh and Avp in pituitary or hypothalamus were altered, consistent with enhanced negative feedback. These findings confirm that impaired peripheral clearance of glucocorticoids can cause ‘relative adrenal insufficiency’ in mice, an observation with important implications for patients with critical illness or hepatic failure, and for patients receiving 5α-reductase inhibitors for prostatic disease.

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Elisa Villalobos University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

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Allende Miguelez-Crespo University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Ruth A Morgan University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Scotland’s Rural College, The Roslin Institute, Easter Bush Campus, United Kingdom

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Lisa Ivatt University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Mhairi Paul University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Joanna P Simpson University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Natalie Z M Homer University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Dominic Kurian The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Easter Bush Campus, Edinburgh, United Kingdom

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Judit Aguilar The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Easter Bush Campus, Edinburgh, United Kingdom

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Rachel A Kline The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Easter Bush Campus, Edinburgh, United Kingdom

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Thomas M Wishart The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Easter Bush Campus, Edinburgh, United Kingdom

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Nicholas M Morton University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Centre for Systems Health and Integrated Metabolic Research, Nottingham Trent University, Nottingham, United Kingdom

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Roland H Stimson University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Ruth Andrew University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Brian R Walker University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

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Mark Nixon University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Glucocorticoids modulate glucose homeostasis, acting on metabolically active tissues such as liver, skeletal muscle, and adipose tissue. Intracellular regulation of glucocorticoid action in adipose tissue impacts metabolic responses to obesity. ATP-binding cassette family C member 1 (ABCC1) is a transmembrane glucocorticoid transporter known to limit the accumulation of exogenously administered corticosterone in adipose tissue. However, the role of ABCC1 in the regulation of endogenous glucocorticoid action and its impact on fuel metabolism has not been studied. Here, we investigate the impact of Abcc1 deficiency on glucocorticoid action and high-fat-diet (HFD)-induced obesity. In lean male mice, deficiency of Abcc1 increased endogenous corticosterone levels in skeletal muscle and adipose tissue but did not impact insulin sensitivity. In contrast, Abcc1-deficient male mice on HFD displayed impaired glucose and insulin tolerance, and fasting hyperinsulinaemia, without alterations in tissue corticosterone levels. Proteomics and bulk RNA sequencing revealed that Abcc1 deficiency amplified the transcriptional response to an obesogenic diet in adipose tissue but not in skeletal muscle. Moreover, Abcc1 deficiency impairs key signalling pathways related to glucose metabolism in both skeletal muscle and adipose tissue, in particular those related to OXPHOS machinery and Glut4. Together, our results highlight a role for ABCC1 in regulating glucose homeostasis, demonstrating diet-dependent effects that are not associated with altered tissue glucocorticoid concentrations.

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