Biomedical subjects

Jonathan R Seckl

Publications and source records attributed to Jonathan R Seckl.

At least 19 recordsLinked to original sources

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

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↗

PubMed2004

Mice deficient in 11beta-hydroxysteroid dehydrogenase type 1 lack bone marrow adipocytes, but maintain normal bone formation.

Glucocorticoids (GCs) exert potent, but poorly characterized, effects on the skeleton. The cellular activity of GCs is regulated at a prereceptor level by 11beta-hydroxysteroid dehydrogenases (11betaHSDs). The type 1 isoform, which predominates in bone, functions as a reductase in intact cells and regenerates active cortisol (corticosterone) from circulating inert 11-keto forms. The aim of the present study was to investigate the role of this intracrine activation of GCs on normal bone physiology in vivo using mice deficient in 11betaHSD1 (HSD1(-/-)). The HSD1(-/-) mice exhibited no significant changes in cortical or trabecular bone mass compared with wild-type (Wt) mice. Aged HSD1(-/-) mice showed age-related bone loss similar to that observed in Wt mice. Histomorphometric analysis showed similar bone formation and bone resorption parameters in HSD1(-/-) and Wt mice. However, examination of bone marrow composition revealed a total absence of marrow adipocytes in HSD1(-/-) mice. Cells from Wt and HSD1(-/-) mice exhibited similar growth rates as well as similar levels of production of osteoblastic markers. The adipocyte-forming capacity of in vitro cultured bone marrow stromal cells and trabecular osteoblasts was similar in HSD1(-/-) and Wt mice. In conclusion, our results suggest that 11betaHSD1 amplification of intracellular GC actions in mice may be required for bone marrow adipocyte formation, but not for bone formation. The clinical relevance of this observation remains to be determined.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2004

Size of the neocerebellar vermis is associated with cognition in healthy elderly men.

Cerebellar volumes show small positive correlations with cognitive ability in young adults, but no studies have examined this relationship in older adults. Furthermore, no studies have examined relationships between sizes of subareas of the cerebellum and cognitive ability. We hypothesized that size of the two areas of the neocerebellar vermis would correlate with a battery of eight cognitive tests in 50 men aged 65-70. Size of the neocerebellar areas of the vermis correlated positively with several cognitive tests (r's=.29-.37, p<.05), whilst sizes of other parts of the vermis did not correlate with any cognitive tests. Total cerebellar volumes correlated significantly with a test of nonverbal reasoning (r=.030, p=.42). These findings suggest a specific association of neocerebellar vermis size with variations in cognitive ability in older adults.

Aged↗

PubMed2004

11beta-hydroxysteroid dehydrogenases: changing glucocorticoid action.

11beta-hydroxysteroid dehydrogenases (11beta-HSDs) catalyse the interconversion of active cortisol and inert cortisone. Two isozymes have been discovered, each with unique properties and powerful biological roles. 11beta-HSD2 potently inactivates cortisol, protecting key tissues. By contrast, 11beta-HSD1 regenerates cortisol, amplifying its actions in liver, fat and brain. Overexpression of this isozyme may contribute to the pathogenesis of the metabolic syndrome. Its inhibition is a potential therapeutic target for both metabolic and glucocorticoid-associated CNS disorders.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2004

11beta-hydroxysteroid dehydrogenase type 1 as a modulator of glucocorticoid action: from metabolism to memory.

Increases in plasma cortisol and glucocorticoid pharmacotherapy cause myriad adverse effects from obesity and diabetes to impairments in memory. The common metabolic syndrome phenotypically resembles the rare disorder Cushing's syndrome, but plasma cortisol levels are usually normal. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyses the regeneration of active glucocorticoids (cortisol and corticosterone) from inert 11-keto forms in specific tissues, notably liver, adipose and brain. Recent work shows that obese humans and rodents have increased 11beta-HSD1 activity selectively in adipose tissue. By locally amplifying glucocorticoid action, this increase in activity might explain the Cushing's syndrome/metabolic syndrome paradox. Indeed, mice deficient in 11beta-HSD1 resist both the metabolic syndrome that develops with dietary obesity and glucocorticoid-associated cognitive impairments that develop with ageing. The ongoing development of selective 11beta-HSD1 inhibitors affords the opportunity to explore a new approach to some major common disorders.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2004

11Beta-hydroxysteroid dehydrogenase type 1 activity in medial vestibular nucleus and cerebellum after unilateral vestibular deafferentation in the rat.

In the early stages of vestibular compensation (VC) (the behavioural recovery that follows unilateral vestibular deafferentation), neurons in the medial vestibular nucleus (MVN) on the lesioned side develop a sustained up-regulation of their intrinsic excitability. This plasticity is dependent on the activation of glucocorticoid receptors, which presumably occurs during the acute stress response that accompanies the vestibular deafferentation symptoms. Recent studies have established that the access of glucocorticoids to their intracellular receptors in brain is potently modulated by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which catalyses the generation of active glucocorticoids from their inert 11-keto forms. In this study, we investigated the presence of 11beta-HSD1 bioactivity, and possible changes in activity in the early stage after vestibular deafferentation, in the cerebellar nodulus and uvula, the flocculus/paraflocculus (F/PF) complex and the MVN of the rat. 11beta-HSD1 activity was found in each of these brain areas, with especially high levels of activity in the F/PF complex. No differences were found in the level of 11beta-HSD1 activity in these brain areas between control rats, sham-operated rats and rats that underwent VC for 4 h after unilateral vestibular deafferentation. These findings demonstrate 11beta-HSD1 bioactivity in the MVN and vestibulocerebellum, but exclude the possibility that changes in 11beta-HSD1 activity occur in the early period after deafferentation, over the time when changes in MVN neuronal properties take place.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2004

Glucocorticoid programming.

Epidemiological evidence suggests that an adverse fetal environment permanently programs physiology, leading to increased risks of cardiovascular, metabolic, and neuroendocrine disorders in adulthood. Prenatal glucocorticoid excess or stress might link fetal maturation and adult pathophysiology. In a variety of animal models, prenatal glucocorticoid exposure or inhibition of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the fetoplacental "barrier" to maternal glucocorticoids, reduces birth weight and causes permanent hypertension, hyperglycemia, and increased hypothalamic-pituitary-adrenal axis (HPA) activity and behavior resembling anxiety. In humans, 11beta-HSD2 gene mutations cause low birth weight and reduced placental 11beta-HSD2 activity associated with intrauterine growth retardation. Low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors; key is the glucocorticoid receptor itself. Differential programming of the glucocorticoid receptor in different tissues reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the glucocorticoid receptor gene. Overall, the data suggest that either pharmacological or physiological exposure to excess glucocorticoids prenatally programs pathologies in adult life.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗

PubMed2004

Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites.

Environmental conditions in early life permanently alter the development of glucocorticoid receptor gene expression in the hippocampus and hypothalamic-pituitary-adrenal responses to acute or chronic stress. In part, these effects can involve an activation of ascending serotonergic pathways and subsequent changes in the expression of transcription factors that might drive glucocorticoid receptor expression in the hippocampus. This paper summarizes the evidence in favor of these pathways as well as recent studies describing regulatory targets within the chromatin structure of the promoter region of the rat hippocampal glucocorticoid receptor gene.

Animals↗