Brian R Walker

The University of Edinburgh, Edinburgh, Scotland, United Kingdom

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Publications (301)1516 Total impact

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    BMJ Open 01/2015; 5(1):e006854-e006854. DOI:10.1136/bmjopen-2014-006854 · 2.06 Impact Factor
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    ABSTRACT: High glucocorticoid levels induced by stress enhance the memory of fearful events and may contribute to the development of anxiety and posttraumatic stress disorder. In contrast, elevated glucocorticoids associated with ageing impair spatial memory. We have previously shown that pharmacological inhibition of the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves spatial memory in aged mice. However, it is not known whether inhibition of 11β-HSD1 will have any beneficial effects on contextual fear memories in aged mice. Here, we examined the effects of UE2316, a selective 11β-HSD1 inhibitor which accesses the brain, on both spatial and contextual fear memories in aged mice using a vehicle-controlled crossover study design. Short-term UE2316 treatment improved spatial memory in aged mice, an effect which was reversed when UE2316 was substituted with vehicle. In contrast, contextual fear memory induced by foot-shock conditioning was significantly reduced by UE2316 in a non-reversible manner. When the order of treatment was reversed following extinction of the original fear memory, and a second foot-shock conditioning was given in a novel context, UE2316 treated aged mice (previously on vehicle) now showed increased fear memory compared to vehicle-treated aged mice (previously on UE2316). Renewal of the original extinguished fear memory triggered by exposure to a new environmental context may explain these effects. Thus 11β-HSD1 inhibition reverses spatial memory impairments with ageing while reducing the strength and persistence of new contextual fear memories. Potentially this could help prevent anxiety-related disorders in vulnerable elderly individuals. Copyright © 2014. Published by Elsevier Ltd.
    Neuropharmacology 12/2014; 91. DOI:10.1016/j.neuropharm.2014.12.005 · 4.82 Impact Factor
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    ABSTRACT: Context and objective: 11beta-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyses regeneration of cortisol in liver, adipose tissue and skeletal muscle, making a substantial contribution to circulating cortisol as demonstrated in humans by combining stable isotope tracer infusion with arteriovenous sampling. In brain, 11βHSD1 is a potential therapeutic target implicated in age-associated cognitive dysfunction. We aimed to quantify brain 11βHSD1 activity, both to assess its contribution to systemic cortisol/cortisone turnover and to develop a tool for measuring 11βHSD1 in dementia and following administration of 11βHSD1 inhibitors. Design, setting and participants: With ethical approval and informed consent, 8 healthy men aged 38.1years (sd 16.5) underwent an ECG-gated phase-contrast magnetic resonance scan to quantify internal jugular vein blood flow and were infused with 1,2 [(2)H]2-cortisone and 9,11,12,12 [(2)H]4-cortisol for 3 hours before samples were obtained from the internal jugular vein and an arterialized hand vein. Steroids were quantified by liquid chromatography-tandem mass spectrometry. Main outcome measures and results: Steady state tracer enrichments were achieved and systemic indices of cortisol/cortisone interconversion were consistent with previous studies in healthy men, however there was no measurable release or production of cortisol, 9,12,12 [(2)H]3-cortisol or cortisone into the internal jugular vein. Conclusions: Although cerebral 11βHSD1 reductase activity may be greater in cognitively impaired patients, in healthy men any contribution of 11βHSD1 in brain to systemic cortisol/cortisone turnover is negligible. The influence of 11βHSD1 in brain is likely confined to subregions, notably the hippocampus. Alternative approaches are required to quantify pharmacodynamics effects of 11βHSD1 inhibitors in human brain.
    Journal of Clinical Endocrinology &amp Metabolism 11/2014; 100(2):jc20143277. DOI:10.1210/jc.2014-3277 · 6.31 Impact Factor
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    ABSTRACT: Background/Objectives Tissue-specific glucocorticoid metabolism is altered in obesity, and may increase cardiovascular risk. This dysregulation is normalized by short-term calorie restriction and weight loss, an effect that varies with dietary macronutrient composition. However, tissue-specific glucocorticoid metabolism has not been studied during long-term (> 6 months) dietary interventions. Therefore our aim was to test whether long-term dietary interventions, either a Paleolithic-type diet (PD) or a diet according to Nordic nutrition recommendations (NNR) could normalize tissue-specific glucocorticoid metabolism in overweight and obese women.Subjects/Methods Forty-nine overweight/obese postmenopausal women were randomized to a Paleolithic diet or a diet according to Nordic nutrition recommendations for 24 months. At baseline, 6 and 24 months anthropometric measurements, insulin sensitivity, excretion of urinary glucocorticoid metabolites in 24-hour collections, conversion of orally administered cortisone to plasma cortisol and transcript levels of 11βHSD1 in subcutaneous adipose tissue were studied.ResultsBoth diet groups achieved significant and sustained weight loss. Weight loss with the PD was greater than on NNR diet after 6 months (P<0.001) but similar at 24 months. Urinary measurement of 5α-reductase activity was increased after 24 months in both groups compared with baseline (P<0.001). Subcutaneous adipose tissue 11βHSD1 gene expression decreased at 6 and 24 months in both diet groups (P=0.036). Consistent with increased liver 11βHSD1, conversion of oral cortisone to cortisol increased at 6 months (P=0.023) but was unchanged compared with baseline by 24 months.Conclusions Long-term weight loss in postmenopausal women has tissue-specific and time-dependent effects on glucocorticoid metabolism. This may alter local tissue cortisol exposure contributing to improved metabolic function during weight loss.International Journal of Obesity accepted article preview online, 28 October 2014. doi:10.1038/ijo.2014.188.
    International journal of obesity (2005) 10/2014; DOI:10.1038/ijo.2014.188 · 5.22 Impact Factor
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    ABSTRACT: Progression and severity of type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic β-cell damage. Glucocorticoids (GCs) are highly effective anti-inflammatory agents but have been precluded in type 1 diabetes and in islet transplantation protocols because they exacerbated insulin resistance and suppressed β-cell insulin secretion at the high-doses employed clinically. In contrast, physiological-range elevation of GC action within β-cells ameliorated lipotoxic β-cell failure in transgenic mice overexpressing the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (MIP-HSD1(tg/+) mice). Here, we tested the hypothesis that elevated β-cell 11beta-HSD1 protects against the β-cell destruction elicited by streptozotocin (STZ), a toxin that dose-dependently mimics aspects of inflammatory and autoimmune β-cell destruction. MIP-HSD1(tg/+) mice exhibited an episodic protection from the severe hyperglycemia caused by a single high dose of STZ associated with higher and sustained β-cell survival, maintained β-cell replicative potential, higher plasma and islet insulin levels, reduced inflammatory macrophage infiltration and increased anti-inflammatory T regulatory cell content. MIP-HSD1(tg/+) mice also completely resisted mild hyperglycemia and insulitis induced by multiple low-dose STZ administration. In vitro, MIP-HSD1(tg/+) islets exhibited attenuated STZ-induced nitric oxide production, an effect reversed with a specific 11beta-HSD1 inhibitor. GC regeneration selectively within β-cells protects against inflammatory β-cell destruction, suggesting therapeutic targeting of 11beta-HSD1 may ameliorate processes that exacerbate type 1 diabetes and that hinder islet transplantation.
    Frontiers in Endocrinology 10/2014; 5:165. DOI:10.3389/fendo.2014.00165
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    ABSTRACT: 5α-Reductase 1 (5αR1) catalyses A-ring reduction of androgens and glucocorticoids in liver, potentially influencing hepatic manifestations of the Metabolic Syndrome.Male mice, homozygous for a disrupted 5α-R1 allele (5αR1-KO), were studied following metabolic (high fat diet) and fibrotic (carbon-tetrachloride) challenge. The effect of the 5α-reductase inhibitor, finasteride, on metabolism was investigated in male obese Zucker rats.On high fat diet male 5αR1-KO mice demonstrated greater weight gain (21.6±1.4 vs 16.2±2.4 g), hyperinsulinaemia (insulin AUC during glucose tolerance test, 609±103 vs 313±66 ng.ml(-1).min) and hepatic steatosis (liver triglycerides: 136.1±17.0 vs 89.3±12.1 micromol.g(-1)). mRNA transcript profiles in liver were consistent with decreased fatty acid β-oxidation and increased triglyceride storage. 5αR1-KO male mice were more susceptible to fibrosis after CCl4 (37% increase in collagen staining). The non-selective 5α-reductase inhibitor finasteride induced hyperinsulinaemia and hepatic steatosis (10.6±1.2 vs 7.0±1.0 micromol.g(-1)) in obese male Zucker rats, both intact and castrated.5α-R1 deficiency induces insulin resistance and hepatic steatosis, consistent with intra-hepatic accumulation of glucocorticoids, and predisposes to hepatic fibrosis. Hepatic steatosis is independent of androgens in rats. Variations in 5αR1 activity in obesity and with non-selective 5α-reductase inhibition in men with prostate disease may have important consequences for onset and progression of metabolic liver disease.
    Diabetes 09/2014; DOI:10.2337/db14-0249 · 7.90 Impact Factor
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    ABSTRACT: To investigate the potential of therapies which reduce glucocorticoid action in patients with type 2 diabetes we performed a randomised, double-blinded, placebo-controlled crossover study of acute glucocorticoid blockade, using the glucocorticoid receptor antagonist RU38486 (mifepristone) and cortisol biosynthesis inhibitor (metyrapone), in 14 men with type 2 diabetes. Stable isotope dilution methodologies were used to measure the rates of appearance (Ra) of glucose, glycerol and free fatty acids (FFAs), including during a low dose (10mU/m(2)/min) hyperinsulinaemic clamp, and sub-group analysis was conducted in patients with high or low liver fat content measured by magnetic resonance spectroscopy (n=7/group). Glucocorticoid blockade lowered fasting glucose and insulin levels, and improved insulin sensitivity of FFA and glycerol turnover and hepatic glucose production. Amongst this population with type 2 diabetes high liver fat was associated with hyperinsulinaemia, higher fasting glucose levels, peripheral and hepatic insulin resistance, and impaired suppression of FFA oxidation and FFA and glycerol turnover during hyperinsulinaemia. Glucocorticoid blockade had similar effects in those with and without high liver fat. Longer term treatments targeting glucocorticoid action may be useful in type 2 diabetes with and without fatty liver.
    AJP Gastrointestinal and Liver Physiology 08/2014; 307(7). DOI:10.1152/ajpgi.00030.2014 · 3.74 Impact Factor
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    ABSTRACT: 11Beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) locally amplifies active glucocorticoids within specific tissues including in brain. In the hippocampus, 11β-HSD1 messenger RNA increases with aging. Here, we report significantly greater increases in intrahippocampal corticosterone (CORT) levels in aged wild-type (WT) mice during the acquisition and retrieval trials in a Y-maze than age-matched 11β-HSD1(-/-) mice, corresponding to impaired and intact spatial memory, respectively. Acute stress applied to young WT mice led to increases in intrahippocampal CORT levels similar to the effects of aging and impaired retrieval of spatial memory. 11β-HSD1(-/-) mice resisted the stress-induced memory impairment. Pharmacologic inhibition of 11β-HSD1 abolished increases in intrahippocampal CORT levels during the Y-maze trials and prevented spatial memory impairments in aged WT mice. These data provide the first in vivo evidence that dynamic increases in hippocampal 11β-HSD1 regenerated CORT levels during learning and retrieval play a key role in age- and stress-associated impairments of spatial memory.
    Neurobiology of Aging 07/2014; DOI:10.1016/j.neurobiolaging.2014.07.007 · 4.85 Impact Factor
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    ABSTRACT: Background The hypothalamic-pituitary-adrenal (HPA) axis is important for fetal growth and timing of parturition. Maternal obesity is associated with macrosomia (birthweight ⩾4000 g) and prolonged pregnancy (⩾41 weeks). We aimed to characterise HPA axis hormones in obese pregnancy and to test associations with these pregnancy outcomes. Method Fasting cortisol was measured by radioimmunoassay in venous blood at 16, 28 and 36 weeks of gestation in 286 obese (BMI 44.05 ± 3.98 kg/m2) and 137 lean (BMI 22.71 ± 1.66 kg/m2) pregnant women. In subsets (n = 20 obese, 20 lean) we measured corticosteroid binding globulin (CBG) and CRH by radioimmunoassay; progesterone, estradiol (E2), estriol (E3) and sex-hormone-binding-globulin (SHBG) by ELISA; and albumin by bromocresol green binding. Free cortisol levels were calculated using Coolen’s equation. Results Cortisol, CBG, calculated free cortisol, CRH, E2, E3, progesterone and SHBG levels rose similarly during pregnancy in obese and lean, but were significantly lower in obese (p < 0.05). In obese, lower free cortisol at 16 weeks was associated with higher birthweight (r = −0.46, p < 0.05). Cortisol was not associated with labour onset. CRH was significantly lower at 36 weeks in women who delivered at ⩾ 41 weeks and in women with macrosomic babies (p < 0.05); and correlated negatively with gestation at delivery in obese (r = −0.557, p < 0.05). Conclusion Our findings suggest that decreased HPA axis activity in obese pregnancy may be a mechanism underlying macrosomia and prolonged pregnancy.
    07/2014; 4(3):238. DOI:10.1016/j.preghy.2014.03.028
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    ABSTRACT: : Mice lacking the glucocorticoid regenerating enzyme 11β hydroxysteroid dehydrogenase type 1 (11βHSD1), responsible for local regeneration of corticosterone, have increased peri-infarct angiogenesis (Small et al ., 2005) and improved cardiac function (McSweeney et al ., 2010) following myocardial infarction (MI). The aim of the present study was to investigate whether these beneficial outcomes could be reproduced by a pharmacological inhibitor of 11βHSD1, UE2316. MI was induced in 45 male C57Bl6 mice by coronary artery ligation. UE2316 (10 mg/kg/day) or vehicle was administered by osmotic minipump implanted at the time of MI induction. Cardiac function was assessed by high resolution ultrasound at 7 days and 21 days after MI after which tissue was collected for assessment of infarct area (Massons trichrome) and blood vessel density (vessels immunopositive for CD31). An additional group of mice UE2316 was administered orally for 2 weeks prior to MI, followed by implantation of mini-pump as above. Treatment with UE2316 did not result in any alteration in plasma concentration of troponin I at 24 h after MI. However, by 3 weeks after induction of MI ejection fraction (EF) was reduced from 72 ± 5% to 30 ± 3% in vehicle treated animals, but in mice that that received UE2316 from the time of MI, EF was significantly increased to 43 ± 5 mmHg (P < 0.05). Additional treatment prior to induction of MI did not cause a further improvement in EF (43 ± 10%). 7 days after induction of MI, vascular density was increased in the infarct and peri-infarct zone in UE2316 compared to vehicle treated mice (P < 0.05) and this was associated with a reduction in infarct area from from 35 ± 7% LV in vehicle group, to 20 ± 2% LV in U12316 group. These data demonstrate that the beneficial effects of 11βHSD1 genetic deletion can be recapitulated by pharmacological inhibition of this enzyme. Importantly, reduction of infarct size and enhancement of ejection fraction can be achieved by delivery of drug at the time of infarction, supporting potential therapeutic utility of this intervention. This study was supported by the Wellcome Trust (PG-WT091720) and by a BHF Centre of Research Excellence Award.
    Heart (British Cardiac Society) 06/2014; 100(Suppl 3):A118. DOI:10.1136/heartjnl-2014-306118.216 · 6.02 Impact Factor
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    ABSTRACT: Context: Treatment of congenital adrenal hyperplasia (CAH) in childhood focuses on growth and development and adult final height (FH) is a measure of effective treatment. We hypothesized that shorter adults will have more severe underlying disease and worse health outcomes. Methods: This was a cross-sectional analysis of 199 adults with CAH. FH and quality of life were expressed as z-scores adjusted for midparental target height or UK population height. Results: FH correlated inversely with age (men, r = -0.38; women, r = -0.26, P < .01). Men and women had z-scores adjusted for midparental target height of -2 and -1, respectively, and both groups had UK population height z-scores of -1 below the UK population (P < .01). In women, FH was shorter in non-salt-wasting than salt-wasting classic CAH (P < .05) and in moderately affected genotype group B women than either more severely affected groups null and A (P < .01) or the mildest group C (P < .001). Short stature and a higher prevalence of hypertension were observed in classic CAH patients diagnosed late (after 1 y) compared with those diagnosed early and in women treated with glucocorticoid only compared with those treated with both glucocorticoids and mineralocorticoids (P < .05). FH did not associate with insulin sensitivity, lipid profile, adiposity, or quality of life. Conclusions: Adult CAH patients remain short, although height prognosis has improved over time. The shortest adults are those diagnosed late with moderate severity CAH and are at increased risk of adult hypertension; we hypothesize that these patients are exposed in childhood to high androgens and/or excessive glucocorticoids with potential programming of hypertension. Another possibility is inadequate mineralocorticoid treatment early in life in the late-diagnosed patient group. Prospective studies are now required to examine these hypotheses.
    05/2014; 99(8):jc20141486. DOI:10.1210/jc.2014-1486
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    ABSTRACT: 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 2 and 5β-reductase, resulting in compensatory down-regulation 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 compared with wild type control mice, clearance of corticosterone was lower after acute or chronic (8-fold, p<0.05) administration. 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 wild type mice. mRNA levels of GR, 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 in patients with critical illness or hepatic failure, and in patients receiving 5α-reductase inhibitors for prostatic disease.
    Journal of Endocrinology 05/2014; DOI:10.1530/JOE-13-0563 · 3.59 Impact Factor
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    ABSTRACT: Background Black women have lower visceral adipose tissue (VAT) but are less insulin sensitive than white women; the mechanisms responsible are unknown.Objective The study aimed to test the hypothesis that variation in subcutaneous adipose tissue (SAT) sensitivity to glucocorticoids might underlie these differences.Methods Body fatness (dual energy x-ray absorptiometry) and distribution (computerized tomography), insulin sensitivity (SI, intravenous and oral glucose tolerance tests), and expression of 11β-hydroxysteroid dehydrogenase-1 (11HSD1), hexose-6-phosphate dehydrogenase (H6PDH), and glucocorticoid receptor-α (GRα), as well as genes involved in adipogenesis and inflammation were measured in abdominal deep SAT (DSAT), superficial SAT (SSAT), and gluteal SAT (GLUT) depots of 56 normal-weight or obese black and white premenopausal South African (SA) women. We used a combination of univariate and multivariate statistics to evaluate ethnic-specific patterns in adipose gene expression and related body composition and insulin sensitivity measures.ResultsAlthough 11HSD1 activity and mRNA did not differ by ethnicity, GRα mRNA levels were significantly lower in SAT of black compared to white women, particularly in the GLUT depot (0.52±0.21 vs 0.91±0.26 AU, respectively, P<0.01). In black women, lower SAT GRα mRNA levels were associated with increased inflammatory gene transcript levels and abdominal SAT area, and reduced adipogenic gene transcript levels, VAT/SAT ratio and SI. Abdominal SAT 11HSD1 activity associated with increased VAT area and decreased SI in white, but not black women.Conclusions In black SA women, down-regulation of GRα mRNA levels with obesity and reduced insulin sensitivity, possibly via increased SAT inflammation, is associated with reduced VAT accumulation.International Journal of Obesity accepted article preview online, 23 May 2014; doi:10.1038/ijo.2014.94.
    International journal of obesity (2005) 05/2014; 39(2). DOI:10.1038/ijo.2014.94 · 5.22 Impact Factor
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    ABSTRACT: Context: 5α-Reductase (5αR) types 1 and 2 catalyse the A-ring reduction of steroids, including androgens and glucocorticoids. 5α-R inhibitors lower dihydrotestosterone (DHT) in benign prostatic hyperplasia: finasteride inhibits 5αR2; dutasteride inhibits both 5αR2 and 5αR1. In rodents, loss of 5αR1 promotes fatty liver. Objective: To test the hypothesis that inhibition of 5αR1 causes metabolic dysfunction in humans. Design: Double-blind randomised controlled parallel group study. Setting: Clinical research facility. Participants: 46 men (20-85 years) studied before and after intervention. Intervention: Oral dutasteride (0.5 mg daily; n=16), finasteride (5 mg daily; n=16) or control (tamsulosin; 0.4 mg daily; n=14) for 3 months. Main outcome measure: Glucose disposal during a stepwise hyperinsulinaemic euglycaemic clamp. Data are mean (SEM). Results: Dutasteride and finasteride had similar effects on steroid profiles, with reduced urinary androgen and glucocorticoid metabolites, reduced circulating DHT, but no change in plasma or salivary cortisol. Dutasteride, but not finasteride, reduced stimulation of glucose disposal by high dose insulin (dutasteride by -5.7 (3.2) μ mol/kg fat-free mass/min, versus finasteride +7.2 (3.0), and tamsulosin +7.0 (2.0)). Dutasteride also reduced suppression of non-esterified fatty acids by insulin, and increased body fat (by 1.6 (0.6) %). Glucose production and glycerol turnover were unchanged. Consistent with metabolic effects of dutasteride being mediated in peripheral tissues, mRNA for 5αR1 but not 5αR2 was detected in human adipose. Conclusion: Dual inhibition of 5αRs, but not inhibition of 5αR2 alone, modulates insulin sensitivity in human peripheral tissues rather than liver. This may have important implications for patients prescribed dutasteride for prostatic disease.
    The Journal of Clinical Endocrinology and Metabolism 05/2014; 99(8):jc20141395. DOI:10.1210/jc.2014-1395 · 6.31 Impact Factor
  • 04/2014; DOI:10.1530/endoabs.35.OC5.2
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    ABSTRACT: Context. Abnormal cortisol metabolism in Polycystic Ovary Syndrome (PCOS) has been invoked as a cause of secondary activation of the hypothalamic-pituitary-adrenal axis and hence androgen excess. However, this is based on urinary excretion of cortisol metabolites, which cannot detect tissue-specific changes in metabolism and may be confounded by obesity.Objective. To assess cortisol clearance and whole-body and tissue-specific activities of 11ß-HSD1 in PCOS.Design. Case-control study.Setting. Medical center.Patients. 20 overweight-obese unmedicated Caucasian women with PCOS, aged 18-45 yr, and 20 Caucasian controls matched for age, body mass index, body fat distribution, and HSD11B1 genotypes (rs846910 and rs12086634).Main Outcome Measures. Cortisol metabolites were measured in 24 h urine. During steady-state 9,11,12,12-2H4-cortisol infusion, cortisol clearance was calculated and whole-body 11ß-HSD1 activity assessed as rate of appearance of 9,12,12-2H3-cortisol (d3-cortisol). Hepatic 11ß-HSD1 activity was quantified as the generation of plasma cortisol following an oral dose of cortisone. Subcutaneous adipose 11ß-HSD1 activity and mRNA were measured, ex vivo, in biopsies.Results. Urinary cortisol metabolite excretion, deuterated-cortisol clearance and the rate of appearance of d3-cortisol did not differ between PCOS and controls. However, hepatic 11ß-HSD1 conversion of oral cortisone to cortisol was impaired (P< 0.05), whereas subcutaneous abdominal adipose tissue 11ß-HSD1 mRNA levels and activity were increased (P< 0.05) in PCOS women with respect to controls.Conclusions. Tissue-specific dysregulation of 11ß-HSD1 is a feature of PCOS, over and above obesity, whereas increased clearance of cortisol may result from obesity rather than PCOS.
    European Journal of Endocrinology 04/2014; DOI:10.1530/EJE-13-1030 · 3.69 Impact Factor
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    ABSTRACT: Cushing's syndrome, caused by increased production of cortisol, leads to metabolic dysfunction including visceral adiposity, hypertension, hyperlipidaemia and type 2 diabetes. The similarities with the metabolic syndrome are striking and major efforts have been made to find obesity-associated changes in the regulation of glucocorticoid action and synthesis, both at a systemic level and tissue level. Obesity is associated with tissue-specific alterations in glucocorticoid metabolism, with increased activity of the glucocorticoid-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue and decreased conversion of cortisone to cortisol, interpreted as decreased 11βHSD1 activity, in the liver. In addition, genetic manipulation of 11βHSD1 activity in rodents can either induce (by overexpression of Hsd11b1, the gene encoding 11βHSD1) or prevent (by knocking out Hsd11b1) obesity and metabolic dysfunction. Taken together with earlier evidence that non-selective inhibitors of 11βHSD1 enhance insulin sensitivity, these results led to the hypothesis that inhibition of 11βHSD1 might be a promising target for treatment of the metabolic syndrome. Several selective 11βHSD1 inhibitors have now been developed and shown to improve metabolic dysfunction in patients with type 2 diabetes, but the small magnitude of the glucose-lowering effect has precluded their further commercial development.This review focuses on the role of 11βHSD1 as a tissue-specific regulator of cortisol exposure in obesity and type 2 diabetes in humans. We consider the potential of inhibition of 11βHSD1 as a therapeutic strategy that might address multiple complications in patients with type 2 diabetes, and provide our thoughts on future directions in this field.
    Diabetologia 04/2014; 57(6). DOI:10.1007/s00125-014-3228-6 · 6.88 Impact Factor
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    ABSTRACT: Context: Mineralocorticoid receptors (MR) contribute to negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis in rodents. Studies with MR antagonists suggest a similar role in humans. Objective: To establish whether loss-of-function mutations in NR3C2, encoding MR, cause activation of the HPA axis. Design and Setting: A case-control study in members of pedigrees from the PHA1.NET cohort, comprising patients with pseudohypoaldosteronism type 1 (PHA1) who are heterozygous for loss-of-function mutations in NR3C2 and healthy controls who are unaffected family members. Participants: 12 adult patients with PHA1 (6 men, 6 women) and 20 age-matched healthy controls (7 men, 13 women). Results: Patients with PHA1 had higher morning plasma cortisol (816 ± 85 vs 586 ± 50 nmol/L, p=0.02) and increased 24h urinary excretion of cortisol metabolites (985 ± 150 vs 640 ± 46 μ g/mmol creatinine, p=0.03), independently of gender. After adjustment for gender, age, PHA1 diagnosis and percentage body fat, higher plasma cortisol was associated with higher plasma renin, lower serum HDL-cholesterol and higher waist circumference, but not with blood pressure, carotid intima-media thickness or echocardiographic parameters. Conclusions: Haploinsufficiency of MR in PHA1 causes HPA axis activation, providing genetic evidence that MR contributes to negative feedback in the human HPA axis. With limited sample size, initial indications suggest the resulting hypercortisolaemia is related to the severity of MR deficiency and has adverse effects mediated by glucocorticoid receptors on liver lipid metabolism and adipose tissue distribution, but does not adversely affect cardiac and vascular remodelling in the absence of normal signalling through MR.
    The Journal of Clinical Endocrinology and Metabolism 04/2014; 99(8):jc20141420. DOI:10.1210/jc.2014-1420 · 6.31 Impact Factor
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    ABSTRACT: Fuelled by the obesity epidemic, there is considerable interest in the developmental origins of white adipose tissue (WAT) and the stem and progenitor cells from which it arises. Whereas increased visceral fat mass is associated with metabolic dysfunction, increased subcutaneous WAT is protective. There are six visceral fat depots: perirenal, gonadal, epicardial, retroperitoneal, omental and mesenteric, and it is a subject of much debate whether these have a common developmental origin and whether this differs from that for subcutaneous WAT. Here we show that all six visceral WAT depots receive a significant contribution from cells expressing Wt1 late in gestation. Conversely, no subcutaneous WAT or brown adipose tissue arises from Wt1-expressing cells. Postnatally, a subset of visceral WAT continues to arise from Wt1-expressing cells, consistent with the finding that Wt1 marks a proportion of cell populations enriched in WAT progenitors. We show that all visceral fat depots have a mesothelial layer like the visceral organs with which they are associated, and provide several lines of evidence that Wt1-expressing mesothelium can produce adipocytes. These results reveal a major ontogenetic difference between visceral and subcutaneous WAT, and pinpoint the lateral plate mesoderm as a major source of visceral WAT. They also support the notion that visceral WAT progenitors are heterogeneous, and suggest that mesothelium is a source of adipocytes.
    Nature Cell Biology 03/2014; DOI:10.1038/ncb2922 · 20.06 Impact Factor
  • 03/2014; DOI:10.1530/endoabs.34.P249

Publication Stats

12k Citations
1,516.00 Total Impact Points

Institutions

  • 1994–2014
    • The University of Edinburgh
      • • Queen's Medical Research Institute
      • • Centre for Cardiovascular Science
      • • Medical Genetics Unit
      Edinburgh, Scotland, United Kingdom
  • 2013
    • University College London
      Londinium, England, United Kingdom
  • 2006–2011
    • Policlinico S.Orsola-Malpighi
      Bolonia, Emilia-Romagna, Italy
  • 2009
    • University of Gothenburg
      Goeteborg, Västra Götaland, Sweden
  • 2007
    • Centre Hospitalier Universitaire de Bordeaux
      Burdeos, Aquitaine, France
  • 2003–2007
    • University of Helsinki
      • Department of Oral Medicine
      Helsinki, Uusimaa, Finland
    • National Institutes of Health
      • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Bethesda, MD, United States
  • 1993–2003
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom
  • 2002
    • Sahlgrenska University Hospital
      Goeteborg, Västra Götaland, Sweden
  • 2001–2002
    • Umeå University
      • Department of Public Health and Clinical Medicine
      Umeå, Vaesterbotten, Sweden
    • University of Southampton
      • Developmental Origins of Health and Disease
      Southampton, England, United Kingdom