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

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

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Glucocorticoid hormones constitute an integral component of the response to stress, and many of the manifestations of glucocorticoid excess (Cushing's syndrome) are predictable on the basis of their acute effects to raise blood pressure, induce insulin resistance, increase protein catabolism and elevate plasma glucose. However, it appears to be a paradox that the acute lipolytic effect of glucocorticoids is not manifest in long-term weight loss in humans. The effects of glucocorticoids on glucose metabolism are well characterised, involving impaired peripheral glucose uptake and hepatic insulin resistance, and there is mounting evidence that subtle abnormalities in glucocorticoid concentrations in the plasma and/or in tissue sensitivity to glucocorticoids are important in metabolic syndrome. The effects of glucocorticoids on fatty acid metabolism are less well understood than their influence on glucose metabolism. In this article, we review the literature describing the effects of glucocorticoids on fatty acid metabolism, with particular reference to in vivo human studies. We consider the implications for contrasting acute versus chronic effects of glucocorticoids on fat accumulation, effects in different adipose depots and the potential role of glucocorticoid signalling in the pathogenesis and therapy of metabolic syndrome.

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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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Lesley A Hill Departments of Cellular and Physiological Sciences and Obstetrics and Gynaecology, The University of British Columbia, Vancouver, British Columbia, Canada

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Dimitra A Vassiliadi Endocrine Unit, Second Department of Internal Medicine-Research Institute and Diabetes Center, Attiko University Hospital, Athens, Greece

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Ioanna Dimopoulou Endocrine Unit, Second Department of Internal Medicine-Research Institute and Diabetes Center, Attiko University Hospital, Athens, Greece

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Anna J Anderson BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Luke D Boyle BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Alixe H M Kilgour BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Roland H Stimson BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Yoan Machado Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, British Columbia, Canada

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Christopher M Overall Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, British Columbia, Canada

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Brian R Walker BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

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John G Lewis Canterbury Health Laboratories, Christchurch, New Zealand

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Geoffrey L Hammond Departments of Cellular and Physiological Sciences and Obstetrics and Gynaecology, The University of British Columbia, Vancouver, British Columbia, Canada

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Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood and is a serine protease inhibitor family member. Human CBG has a reactive center loop (RCL) which, when cleaved by neutrophil elastase (NE), disrupts its steroid-binding activity. Measurements of CBG levels are typically based on steroid-binding capacity or immunoassays. Discrepancies in ELISAs using monoclonal antibodies that discriminate between intact vs RCL-cleaved CBG have been interpreted as evidence that CBG with a cleaved RCL and low affinity for cortisol exists in the circulation. We examined the biochemical properties of plasma CBG in samples with discordant ELISA measurements and sought to identify RCL-cleaved CBG in human blood samples. Plasma CBG-binding capacity and ELISA values were consistent in arterial and venous blood draining skeletal muscle, liver and brain, as well as from a tissue (adipose) expected to contain activated neutrophils in obese individuals. Moreover, RCL-cleaved CBG was undetectable in plasma from critically ill patients, irrespective of whether their ELISA measurements were concordant or discordant. We found no evidence of RCL-cleaved CBG in plasma using a heat-dependent polymerization assay, and CBG that resists immunoprecipitation with a monoclonal antibody designed to specifically recognize an intact RCL, bound steroids with a high affinity. In addition, mass spectrometry confirmed the absence of NE-cleaved CBG in plasma in which ELISA values were highly discordant. Human CBG with a NE-cleaved RCL and low affinity for steroids is absent in blood samples, and CBG ELISA discrepancies likely reflect structural differences that alter epitopes recognized by specific monoclonal antibodies.

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Dieuwertje C E Spaanderman Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Mark Nixon BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Jacobus C Buurstede Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Hetty H C M Sips Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Maaike Schilperoort Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Eline N Kuipers Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Emma A Backer Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Sander Kooijman Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Patrick C N Rensen Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

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

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Brian R Walker BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Institute for Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

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Onno C Meijer Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Jan Kroon Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Glucocorticoid signaling is context dependent, and in certain scenarios, glucocorticoid receptors (GRs) are able to engage with other members of the nuclear receptor subfamily. Glucocorticoid signaling can exert sexually dimorphic effects, suggesting a possible interaction with androgen sex hormones. We therefore set out to determine the crosstalk between glucocorticoids and androgens in metabolic tissues including white adipose tissue, liver and brown adipose tissue. Thereto we exposed male C57BL/6J mice to elevated levels of corticosterone in combination with an androgen receptor (AR) agonist or an AR antagonist. Systemic and local glucocorticoid levels were determined by mass spectrometry, and tissue expression of glucocorticoid-responsive genes and protein was measured by RT-qPCR and Western blot, respectively. To evaluate crosstalk in vitro, cultured white and brown adipocytes were exposed to a combination of corticosterone and an AR agonist. We found that AR agonism potentiated transcriptional response to GR in vitro in white and brown adipocytes and in vivo in white and brown adipose tissues. Conversely, AR antagonism substantially attenuated glucocorticoid signaling in white adipose tissue and liver. In white adipose tissue, this effect could partially be attributed to decreased 11B-hydroxysteroid dehydrogenase type 1-mediated glucocorticoid regeneration upon AR antagonism. In liver, attenuated GR activity was independent of active glucocorticoid ligand levels. We conclude that androgen signaling modulates GR transcriptional output in a tissue-specific manner.

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Katie J Mylonas University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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Neil A Turner Division of Cardiovascular & Diabetes Research, Leeds Institute of Cardiovascular & Metabolic Medicine (LICAMM), School of Medicine, University of Leeds, Leeds, UK

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Sumia A Bageghni Division of Cardiovascular & Diabetes Research, Leeds Institute of Cardiovascular & Metabolic Medicine (LICAMM), School of Medicine, University of Leeds, Leeds, UK

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Christopher J Kenyon University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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Christopher I White University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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Kieran McGregor University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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Robert A Kimmitt University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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Richard Sulston University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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Valerie Kelly University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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

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Karen E Porter Division of Cardiovascular & Diabetes Research, Leeds Institute of Cardiovascular & Metabolic Medicine (LICAMM), School of Medicine, University of Leeds, Leeds, UK

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Karen E Chapman University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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Gillian A Gray University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

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We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient (Hsd11b1 / ) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid. In bone marrow chimeric mice, neutrophil mobilization was increased when 11β-HSD1 was absent from host cells, but not when absent from donor bone marrow-derived cells. Consistent with a role for 11β-HSD1 in ‘host’ myocardium, gene expression of a subset of neutrophil chemoattractants, including the chemokines Cxcl2 and Cxcl5, was selectively increased in the myocardium of Hsd11b1 / mice relative to WT. SM22α-Cre directed disruption of Hsd11b1 in smooth muscle and cardiomyocytes had no effect on neutrophil recruitment. Expression of Cxcl2 and Cxcl5 was elevated in fibroblast fractions isolated from hearts of Hsd11b1 / mice post MI and provision of either corticosterone or of the 11β-HSD1 substrate, 11-dehydrocorticosterone, to cultured murine cardiac fibroblasts suppressed IL-1α-induced expression of Cxcl2 and Cxcl5. These data identify suppression of CXCL2 and CXCL5 chemoattractant expression by 11β-HSD1 as a novel mechanism with potential for regulation of neutrophil recruitment to the injured myocardium, and cardiac fibroblasts as a key site for intracellular glucocorticoid regeneration during acute inflammation following myocardial injury.

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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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