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Jonathan R Seckl

Publications and source records attributed to Jonathan R Seckl.

At least 19 recordsLinked to original sources
PubMed2006

The role of 11beta-hydroxysteroid dehydrogenases in the brain.

Glucocorticoids have a plethora of effects within the body to maintain homeostasis. In the brain they modify learning, memory and fear behaviours as well as regulating their own secretion by a negative feedback action. 11Beta-hydroxysteroid dehydrogenases (11beta-HSDs) are glucocorticoid metabolising enzymes that modify actions of glucocorticoids in a tissue specific manner. 11Beta-HSD1 regenerates active glucocorticoids from their inactive 11-keto derivatives, hence boosting tissue levels of corticosterone and cortisol. Removal of this enzyme (11beta-HSD1-/- mice) results in apparent lower intra-hippocampal corticosterone levels and reduces glucocorticoid-associated cognitive decline during ageing. This low corticosterone tissue environment is maintained even though there is a hyperactive hypothalamic-pituitary-adrenal axis and elevated basal and stress-induced plasma corticosterone levels. Conversely, the major central effects of 11beta-HSD2 are seen in development, as expression of 11beta-HSD2 is high in fetal and certain parts of the neonate brain, but is confined to a few discrete regions of the adult brain. 11Beta-HSD2 acts as a dehydrogenase, inactivating corticosterone or cortisol through conversion to 11-dehydrocorticosterone and cortisone. Loss of 11beta-HSD2 from the fetus and fetally derived tissues results in altered development of the cerebellum in the neonatal period and a life-long phenotype of anxiety, consistent with early life glucocorticoid programming.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2006

11Beta-hydroxysteroid dehydrogenase type 1--a role in inflammation?

Glucocorticoids are widely used for their potent anti-inflammatory effects. Endogenous glucocorticoids are immunomodulatory and shape both adaptive and innate immune responses. Over the past decade, it has become apparent that an important level of control over endogenous glucocorticoid action is exerted by the 11beta-hydroxysteroid dehydrogenase enzymes. The type 1 enzyme, 11beta-HSD1, reduces inert glucocorticoids into active forms, thereby increasing intracellular ligand availability to receptors. Although 11beta-HSD1 activity has been shown to play an important role in the metabolic actions of glucocorticoids, its role in the immune response has, until recently, remained unclear. Here we review recent evidence pertaining to the role of 11beta-HSD1 in the inflammatory response.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2006

Assessing the HPA axis in patients with pituitary disease: a UK survey.

OBJECTIVE: Assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis following pituitary surgery is necessary to determine the requirement for glucocorticoid replacement therapy, but there remains controversy about the optimum way to measure this. DESIGN AND MEASUREMENTS: Postal questionnaire survey among UK endocrinologists to evaluate the current methods used. RESULTS: The response rate was low (81 out of 598 questionnaires mailed), although 85% were consultants. Fifty-five percent measured 9:00 h plasma cortisol in the immediate postoperative phase. Most carried out definitive testing between 4 and 12 weeks: 36% routinely used the insulin tolerance test (ITT), 59% used the short synacthen test (SST). The 30-min cortisol value was used by 67% as a 'pass' when interpreting the results. Others included cortisol measurement at 60 min (17%) or incremental value (7%). For long-term follow-up of patients not rendered ACTH-deficient by surgery, 64% used the SST for patients who had received radiotherapy. If patients had not had radiotherapy, 42% used the SST, whereas 33% did no routine testing unless the patient was symptomatic or there was evidence of tumour recurrence on imaging. If patients were symptomless but 'failed' the chosen test, 28% still treated the patient with glucocorticoid replacement, 38% retested before treatment and 24% recommended glucocorticoid cover for when unwell or 'stressed'. Fifty-six percent used hydrocortisone at doses of 20 mg/day as replacement therapy. CONCLUSION: Thus, assessment of the HPA axis remains controversial. Although the SST is becoming more popular, there is still considerable variation in the interpretation of results and, in particular, the decision of whether or not to treat with lifelong glucocorticoid replacement therapy.

Adrenocorticotropic Hormone↗
PubMed2005

Polymorphisms in the gene encoding 11B-hydroxysteroid dehydrogenase type 1 (HSD11B1) and lifetime cognitive change.

A rare polymorphism in the gene encoding 11B-hydroxysteroid dehydrogenase type 1 (HSD11B1: rs846911-C/A) has been associated with an increased risk of Alzheimer's disease. We tested the hypothesis that this and 2 other HSD11B1 polymorphisms (rs12086634-G/T and rs846910-A/G) were associated with lifetime cognitive change in humans. Subjects were 194 participants of the Scottish Mental Survey of 1932 who took the same well-validated mental test at age 11 and age 79. The subjects represented the highest and lowest quintiles with respect to cognitive decline between ages 11 and 79. Despite having non-significantly different IQs at age 11, by age 79 the groups had mean (S.D.) IQs of 80.3 (14.1) and 109.6 (9.1), respectively (p<.001). The polymorphism rs846911-C/A was absent from both groups. There were no significant differences in the frequency of polymorphisms of rs12086634-G/T (p=.91) and rs846910-A/G (p=.90) between the groups. We conclude that these variants in HSD11B1 are not significant contributors to the range of cognitive ageing examined here.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2005

Programming the offspring of the pig by prenatal social stress: neuroendocrine activity and behaviour.

This study provides evidence in the pig that stress experienced during gestation has long-lasting effects on offspring daughters, including their maternal behaviour. Thirty-six primiparous sows were divided into control and two groups that were stressed (by social mixing) during either the second (Mix 2) or third (Mix 3) trimester of pregnancy. We found detrimental effects of mixing on the mothers' growth, body lesions, and cortisol secretion, but did not observe any significant effects on reproductive parameters including birth weight. At 60 days of age, 48 daughters were randomly selected from the three treatments: half were challenged using a restraint and isolation test. Then, all were culled and brain tissue was collected. In situ hybridisation measurements showed increased expression of CRH mRNA in the PVN in unrestrained Mix 2 and in the amygdala of Mix 2 and Mix 3 daughters. At 67 days, 24 further daughters were mixed to measure their responses to this social stress. All showed increased salivary cortisol secretion, but Mix 2 and Mix 3 daughters showed a greater and longer response than controls. Finally, all 24 were inseminated and at parturition maternal behaviour was measured. Mix 2 and Mix 3 daughters were more restless and more responsive to piglets that approached the head of the sow, traits which previously have been shown to be a component of abnormal maternal behaviour. Indeed, Mix 2 and Mix 3 daughters also tended to bite at their piglets more than control daughters.

Animals↗
PubMed2005

Plasma cortisol levels, brain volumes and cognition in healthy elderly men.

PURPOSE: In ageing animals, exposure to chronic high levels of glucocorticoids is associated with cognitive impairment and hippocampal atrophy. However, there are few studies examining relationships among glucocorticoids, brain volumes and cognitive function in healthy older humans. This study examined the hypotheses that higher plasma cortisol levels and altered sensitivity to glucocorticoids are associated with worse cognition and more brain atrophy in elderly men. MATERIALS AND METHODS: Ninety-seven healthy men aged 65-70 had plasma cortisol measured at 09:00, 14:30 h, and post-dexamethasone (0.25mg, 09:00 h), and had dermal sensitivity to glucocorticoids measured. They also underwent cognitive testing, with scores adjusted for estimated prior mental ability, and had MRI measurements of intracranial area (a validated estimate of intracranial capacity), and hippocampus, temporal lobe and frontal lobe volumes. RESULTS: Plasma cortisol levels at 09:00 h were significantly and negatively correlated with a summary General Cognitive Factor accounting for 51% of the variance of cognitive function (rho=-0.22, p=0.035), and specific cognitive tests: delayed paragraph recall (rho=-0.28, p=0.036) and processing speed (rho=-0.23, p=0.026). Regional brain volumes adjusted for intracranial area generally did not correlate with cortisol levels. Tissue glucocorticoid sensitivity did not correlate with any measure of cognition or brain volume. CONCLUSIONS: In healthy older men, higher plasma cortisol levels are associated with worse ageing-related overall cognitive change but not ageing-related brain atrophy.

Aged↗
PubMed2005

Genetic manipulation of 11beta-hydroxysteroid dehydrogenases in mice.

11beta-hydroxysteroid dehydrogenases (HSDs) interconvert active 11-hydroxy glucocorticoids (cortisol, corticosterone) and their inert 11-keto derivatives (cortisone, 11-dehydrocorticosterone). 11beta-HSD type 1 is a predominant reductase that regenerates active glucocorticoids in expressing cells, thus amplifying local glucocorticoid action, whereas 11beta-HSD type 2 catalyzes rapid dehydrogenation, potently inactivating intracellular glucocorticoids. Both isozymes thus regulate receptor activation by substrate availability. Spatial and temporal regulation of expression are important determinants of the physiological roles of 11beta-HSDs, with each isozyme exhibiting a distinct, tissue-restricted pattern together with dynamic regulation during development and in response to environmental challenges, including diet and stress. Transgenic approaches in the mouse have contributed significantly toward an understanding of the importance of these prereceptor regulatory mechanisms on corticosteroid receptor activity and have highlighted its potential relevance to human health and disease. Here we discuss current ideas of the physiological roles of 11beta-HSDs, with emphasis on the key contributions made by studies of 11beta-HSD gene manipulation in vivo.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2005

A polygenic model of the metabolic syndrome with reduced circulating and intra-adipose glucocorticoid action.

Despite major advances in understanding monogenic causes of morbid obesity, the complex genetic and environmental etiology of idiopathic metabolic syndrome remains poorly understood. One hypothesis suggests that similarities between the metabolic disease of plasma glucocorticoid excess (Cushing's syndrome) and idiopathic metabolic syndrome results from increased glucocorticoid reamplification within adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1). Indeed, 11beta-HSD-1 is now a major therapeutic target. Because much supporting evidence for a role of adipose 11beta-HSD-1 comes from transgenic or obese rodents with single-gene mutations, we investigated whether the predicted traits of metabolic syndrome and glucocorticoid metabolism were coassociated in a unique polygenic model of obesity developed by long-term selection for divergent fat mass (Fat and Lean mice with 23 vs. 4% fat as body weight, respectively). Fat mice exhibited an insulin-resistant metabolic syndrome including fatty liver and hypertension. Unexpectedly, Fat mice had a marked intra-adipose (11beta-HSD-1) and plasma glucocorticoid deficiency but higher liver glucocorticoid action. Furthermore, metabolic disease was exacerbated only in Fat mice when challenged with exogenous glucocorticoids or a high-fat diet. Our data suggest that idiopathic metabolic syndrome might associate with such a novel pattern of glucocorticoid action and sensitivity in humans, with implications for tissue-specific therapeutic targeting of 11beta-HSD-1.

Adipose Tissue↗
PubMed2005

Adipocyte-specific glucocorticoid inactivation protects against diet-induced obesity.

Local glucocorticoid (GC) action depends on intracellular GC metabolism by 11beta-hydroxysteroid dehydrogenases (11betaHSDs). 11betaHSD1 activates GCs, while 11betaHSD2 inactivates GCs. Adipocyte-specific amplification of GCs through transgenic overexpression of 11betaHSD1 produces visceral obesity and the metabolic syndrome in mice. To determine whether adipocyte-specific inactivation of GCs protects against this phenotype, we created a transgenic model in which human 11betaHSD2 is expressed under the control of the murine adipocyte fatty acid binding protein (aP2) promoter (aP2-h11betaHSD2). Transgenic mice have increased 11betaHSD2 expression and activity exclusively in adipose tissue, with the highest levels in subcutaneous adipose tissue, while systemic indexes of GC exposure are unchanged. Transgenic mice resist weight gain on high-fat diet due to reduced fat mass accumulation. This improved energy balance is associated with decreased food intake, increased energy expenditure, and improved glucose tolerance and insulin sensitivity. Adipose tissue gene expression in transgenic mice is characterized by decreased expression of leptin and resistin and increased expression of adiponectin, peroxisome proliferator-activated receptor gamma, and uncoupling protein 2. These data suggest that reduction of active GCs exclusively in adipose tissue is an important determinant of a favorable metabolic phenotype with respect to energy homeostasis and the metabolic syndrome.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2005

Recurrent dizzy spells: all in the head!

Hypoglycaemia is an uncommon manifestation of hypopituitarism in non-diabetic adults. A 47-year-old woman with Cushing's disease was treated with bilateral adrenalectomy and pituitary radiotherapy following unsuccessful trans-sphenoidal surgery. Twenty years later, she presented with a tonic-clonic seizure and recurrent symptoms suggestive of spontaneous hypoglycaemia. Her symptoms continued despite manipulation of her glucocorticoid replacement therapy. Recurrent severe hypoglycaemia resolved after identification and treatment of her concomitant growth hormone deficiency. In patients with hypopituitarism, undiagnosed growth hormone deficiency can influence glucose metabolism and predispose to severe hypoglycaemia.

Disease Susceptibility↗
PubMed2004

Reduced adipose glucocorticoid reactivation and increased hepatic glucocorticoid clearance as an early adaptation to high-fat feeding in Wistar rats.

Altered peripheral glucocorticoid metabolism may be important in the pathogenesis of obesity in humans and animal models. Genetically obese Zucker rats, Lep/ob mice, and obese humans exhibit increased regeneration of active glucocorticoids selectively in adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) and increased glucocorticoid clearance by hepatic A-ring reductases. We have examined whether dietary obesity in rats induces the same changes in glucocorticoid metabolism. Male Wistar rats were weaned onto high-fat (HF; 45% kcal from fat) or control (10% fat) diets. After 3 wk, HF rats showed no differences in weight but were glucose intolerant, had lower 11beta-HSD-1 activity in liver (3.8 +/- 0.2 vs. 4.9 +/- 0.2 pmol product/min.mg protein; P <0.01), sc fat (0.03 +/- 0.01 vs. 0.09 +/- 0.01 pmol product/min.mg protein; P <0.01), and omental fat (0.02 +/- 0.001 vs. 0.03 +/- 0.003 pmol/ product/min.mg protein; P <0.05) and higher hepatic 5beta-reductase activity (0.26 +/- 0.05 vs. 0.10 +/- 0.007 pmol product/min.mg protein; P <0.05). After 20 wk, HF rats were obese, hyperglycemic, and hyperinsulinemic, but differences in 11beta-HSD-1 and 5beta-reductase activities were no longer apparent. Mature male rats given HF diets for 24 or 72 h showed increased hepatic 5beta-reductase activity and a trend for decreased sc adipose 11beta-HSD-1 activity. Dietary obesity is not accompanied by the changes in 11beta-HSD-1 and 5beta-reductase expression and activity observed in genetically obese rodents. Acute exposure to HF diet alters glucocorticoid metabolism, predicting lower hepatic and adipose intracellular glucocorticoid concentrations, which may be a key mechanism protecting against the metabolic complications of obesity.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2004

Differential regulation of variant glucocorticoid receptor mRNAs in the rat hippocampus by the antidepressant fluoxetine.

Adult rats were given antidepressant drugs orally. Fluoxetine, but not moclobemide, venlafaxine, tianeptine or desipramine, increased total glucocorticoid receptor (GR) mRNA in the hippocampus after 4 weeks. Further examination revealed that GR mRNA containing the brain-specific exon 1(7) was increased across all hippocampal subregions. In contrast, expression of the major exon 1(10) and another brain-specific exon 1(5)-containing GR mRNAs were unchanged. Tissue-specific first exon usage may contribute to the differential regulation of GR by fluoxetine in brain subregions.

Animals↗
PubMed2004

Epigenetic programming by maternal behavior.

Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.

Acetylation↗
PubMed2004

Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats.

Epidemiological studies linking low birth weight and subsequent cardiometabolic disease have given rise to the hypothesis that events in fetal life permanently program subsequent cardiovascular risk. The effects of fetal programming may not be limited to the first-generation offspring. We have explored intergenerational effects in the dexamethasone-programmed rat, a model in which fetal exposure to excess glucocorticoid results in low birth weight with subsequent adult hyperinsulinemia and hyperglycemia underpinned by increased activity of the key hepatic gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK). We found that the male offspring of female rats that had been exposed prenatally to dexamethasone, but were not manipulated in their own pregnancy, also had reduced birth weight (5.66 +/- 0.06 vs. 6.12 +/- 0.06 g, P < 0.001), glucose intolerance, and elevated hepatic PEPCK activity (5.7 +/- 0.6 vs. 3.3 +/- 0.2 nmol.min(-1).mg protein(-1), P < 0.001). These effects resolved in a third generation. Similar intergenerational programming was observed in offspring of male rats exposed prenatally to dexamethasone mated with control females. The persistence of such programming effects through several generations, transmitted by either maternal or paternal lines, indicates the potential importance of epigenetic factors in the intergenerational inheritance of the "programming phenotype" and provides a basis for the inherited association between low birth weight and cardiovascular risk factors.

Animals↗
PubMed2004

Metabolic syndrome without obesity: Hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice.

In obese humans and rodents there is increased expression of the key glucocorticoid (GC) regenerating enzyme, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), in adipose tissue. This increased expression appears to be of pathogenic importance because transgenic mice overexpressing 11beta-HSD1 selectively in adipose tissue exhibit a full metabolic syndrome with visceral obesity, dyslipidemia, insulin-resistant diabetes, and hypertension. In this model, while systemic plasma GC levels are unaltered, GC delivery to the liver via the portal vein is increased. 11beta-HSD1 is most highly expressed in liver where inhibition or deficiency of its activity improves glucose and lipid homeostasis. To determine the potential contribution of elevated intrahepatic GCs alone toward development of insulin-resistant syndromes we generated transgenic mice expressing increased 11beta-HSD1 activity selectively in the liver under transcriptional control of hepatic regulatory sequences derived from the human apoE gene (apoE-HSD1). Transgenic lines with 2- and 5-fold-elevated 11beta-HSD1 activity exhibited mild insulin resistance without altered fat depot mass. ApoE-HSD1 transgenic mice exhibited fatty liver and dyslipidemia with increased hepatic lipid synthesis/flux associated with elevated hepatic LXRalpha and PPARalpha mRNA levels as well as impaired hepatic lipid clearance. Further, apoE-HSD1 transgenic mice have a marked, transgene-dose-associated hypertension paralleled by incrementally increased liver angiotensinogen expression. These data suggest that elevated hepatic expression of 11beta-HSD1 may relate to the pathogenesis of specific fatty liver, insulin-resistant, and hypertensive syndromes without obesity in humans as may occur in, for example, myotonic dystrophy, and possibly, the metabolically obese, normal-weight individual.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2004

11Beta-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics.

In aging humans and rodents, inter-individual differences in cognitive function have been ascribed to variations in long-term glucocorticoid exposure. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates the active glucocorticoid cortisol from circulating inert cortisone, thus amplifying intracellular glucocorticoid levels in some tissues. We show that 11beta-HSD1, but not 11beta-HSD2, mRNA is expressed in the human hippocampus, frontal cortex, and cerebellum. In two randomized, double-blind, placebo-controlled crossover studies, administration of the 11beta-HSD inhibitor carbenoxolone (100 mg three times per day) improved verbal fluency (P < 0.01) after 4 weeks in 10 healthy elderly men (aged 55-75 y) and improved verbal memory (P < 0.01) after 6 weeks in 12 patients with type 2 diabetes (52-70 y). Although carbenoxolone has been reported to enhance hepatic insulin sensitivity in short-term studies, there were no changes in glycemic control or serum lipid profile, nor was plasma cortisol altered. 11beta-HSD1 inhibition may be a new approach to prevent/ameliorate cognitive decline.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2004

Down-regulation of adipose 11beta-hydroxysteroid dehydrogenase type 1 by high-fat feeding in mice: a potential adaptive mechanism counteracting metabolic disease.

The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) amplifies intracellular glucocorticoid action in vivo. 11beta-HSD-1 activity is increased in adipose tissues of obese humans and genetically obese rodents, providing a mechanistic basis for the similarities between metabolic disease arising from high circulating glucocorticoids (Cushing's syndrome) and idiopathic obesity/metabolic syndrome where plasma glucocorticoids are typically unaltered. Fat-specific overexpression of 11beta-HSD-1 produces a metabolic syndrome in mice, whereas 11beta-HSD-1 null mice resist high-fat diet (HF)-induced visceral obesity and its metabolic consequences. Here we compared the effects of chronic (18 wk) HF feeding on adipose 11beta-HSD-1 activity in strains of mice that are either resistant (A/J) or prone (C57BL/6J) to metabolic disease. 11beta-HSD-1 activity was highest in sc fat, followed by epididymal fat, with lowest activity in the mesenteric visceral depot of both strains. 11beta-HSD-1 activity was lower in white adipose tissues of A/J compared with C57BL/6J mice. Chronic HF feeding unexpectedly caused a down-regulation of 11beta-HSD-1 in adipose tissues of both strains, despite comparable adiposity. However, A/J mice down-regulated adipose 11beta-HSD-1 to a significantly lower level than C57BL/6J mice in white and thermogenic brown adipose tissues. We propose that a lower adipose 11beta-HSD-1 set point affords a metabolic protection to A/J mice. Adaptive down-regulation of adipose 11beta-HSD-1 in response to chronic HF represents a novel mechanism that may counteract metabolic disease.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗