Endocrine Abstracts

Regulation of the epithelial sodium channel (ENaC) trafficking in cells of the distal nephron is of major importance in the control of sodium reabsorption. Mutations in the genes compromising the molecular pathway by which corticosteroids regulate ENaC sodium reabsorption cause several hypertensive syndromes in humans. The molecular events underpinning ENaC exo- and endocytosis and the hormonal effects on ENaC trafficking are poorly understood. To start elucidating these pathw...

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) is a key enzyme which amplifies intracellular levels of active glucocorticoids within specific tissues, including the brain. The hippocampus highly expresses both corticosteroid receptors and 11beta-HSD-1, making it a prime target for glucocorticoid actions. This brain region plays an important role in fear/anxiety behaviours and learning and memory. We examined the anxiety-related behaviours (elevated plus maze and ope...

Cellular sensitivity to circulating glucocorticoids is critical and is principally determined by the level of glucocorticoid receptor (GR). GR expression is most potently regulated by glucocorticoids themselves, although the mechanism is unknown. The rat GR gene encodes at least eleven alternate and untranslated exons 1, eight of which lie in a 3kb CpG island close to exon 2. We have recently shown that individual exons 1 are subject to tissue specific expression and regulatio...

Metabolic Syndrome (visceral obesity, insulin resistance, type2 diabetes) resembles Cushing's syndrome, but lacks elevated circulating cortisol levels. This has engendered the hypothesis that excessive local glucocorticoid regeneration, resulting from elevated adipose 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) underlies the Metabolic Syndrome. We report that 11beta-HSD-1 nullizygosity (11beta-HSD-1-/-) reduced intra-adipose corticosterone levels and i...

Epidemiological evidence suggests that an adverse fetal environment permanently programmes physiology leading to increased risks of cardiovascular, metabolic, neuroendocrine and psychiatric disorders in adulthood. Prenatal glucocorticoid excess might link fetal maturation and adult pathophysiology. In a variety of animal models, prenatal stress or exposure to synthetic glucocorticoid which cross the placenta reduces birth weight and causes permanent hypertension, hyperglycaemi...

Epigenetic dysregulation may be one mechanism underpinning the link between early life conditions and later cardiometabolic risk. In animal models, environmental manipulations including modified maternal diet change DNA methylation and offspring phenotype. Manipulations altering the epigenetic state reverse the phenotype suggesting causality. We have previously reported higher blood pressure (BP) and cortisol in an adult cohort whose mothers were advised to eat a high-protein,...

Mechanisms underlying the association of low birth weight with the metabolic syndrome in adults remain poorly understood. Epidemiological studies suggest that obesity is not programmed by early life events, but amplifies the risks of intra-uterine growth retardation. We have explored the effects of dietary obesity in rats in which features of the metabolic syndrome have been programmed by prenatal dexamethasone.16 pregnant Wistar rats were treated with d...

Glucocorticoids have profound effects in development, altering cell proliferation, differentiation, migration and network formation. It has been shown that the developing fetus is protected from high maternal glucocorticoid levels by the presence of 11beta-HSD2 in the placenta and if this enzyme is inhibited, programmed changes of adult health are observed (hypertension, hyperglycaemia, insulin resistance). The developing brain is a sensitive target for glucocorticoids and hen...

Prenatal dexamethasone (dex) administration in rats retards foetal growth, and programmes hyperinsulinaemia and glucose intolerance in adult offspring. This can be explained in part by increased hepatic gluconeogenesis, due to up-regulated glucocorticoid receptor (GR) expression, but may also involve impaired peripheral glucose disposal. In this model, we previously showed no increase in skeletal muscle GR, and have now examined GR and key metabolic genes in adipose tissue.</...

The Metabolic Syndrome (insulin resistance, hyperglycaemia, dyslipidaemia, hypertension) amplified by visceral obesity resembles Cushing's but plasma cortisol levels are not usually elevated. To explain this paradox altered tissue sensitivity to glucocorticoids has been invoked. 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) reactivates cortisone to cortisol, thus amplifying local glucocorticoid action. An adipose-selective increase in 11b-HSD1 may underlie the Metabolic S...