Endocrine Abstracts

5alpha-Reductase 1 (5aR1) catalyses A-ring reduction of glucocorticoids and androgens. We previously demonstrated that transgenic disruption of 5aR1 predisposes male mice to fatty liver and insulin resistance when challenged with a high-fat diet. Here, we have dissected the contributions of androgens and glucocorticoids to the metabolic phenotype using 2 models of enzyme inhibition (trangenesis and pharmacology).Female 5aR1−/− mice (KO) and w...

Hepatic A-ring reduction of glucocorticoids is enhanced in obesity, perhaps contributing to compensatory activation of the hypothalamic-pituitary-adrenal axis and adrenal androgen excess. One pathway activated is the formation of tetrahydro metabolites by two sequential steps catalysed by 5beta-reductase (5bR) followed by 3alpha-hydroxysteroid dehydrogenases (3HSD). However, regulation of these enzymes is understood poorly. 5bR and 3HSD are also involved in the conversion of c...

11HSD1 regenerates cortisol from cortisone and maintains glucocorticoid receptor (GR) activation. Adipose-specific transgenic 11HSD1 overexpression in mice causes obesity, insulin resistance, and hypertension (reflecting increased adipose angiotensinogen); however, the effect depended upon local GR expression. In human obesity, 11HSD1 activity is increased similarly in biopsied adipose, but the impact remains uncertain. We tested whether increased adipose 11HSD1 activity in ob...

Obesity is associated with hypothalamic-pituitary-adrenal (HPA) axis activation. In obese humans and leptin-resistant obese Zucker rats, we have reported increased excretion of A-ring reduced glucocorticoid metabolites. We have now investigated regulation of hepatic A-ring reductases in the obese Zucker rat.Lean and obese Zucker rats (9wks) were studied either: 3-weeks after adrenalectomy (ADX) or sham surgery; or after 3-weeks treatment with metformin ...

Glucocorticoids are potentially important in obesity; recent data suggest both circulating levels and tissue-specific changes in glucocorticoid responsiveness and metabolism may influence their effect. In obese Zucker rats, the phenotype is ameliorated by adrenalectomy, and shows the same pattern of altered glucocorticoid metabolism as in human obesity. However, previous reports suggest hepatic glucocorticoid receptor (GR) binding is impaired. We have now explored expression o...

Previously, we have shown that 5α-tetrahydrocorticosterone (5αTHB), the reduced metabolite of corticosterone (B, the main glucocorticoid in rodents), binds to the glucocorticoid receptor, suppresses the HPA axis but has weak in vivo effects on adipose tissue and liver metabolism. Here we have compared the anti-inflammatory effects of B and 5αTHB in three in vitro and in vivo experiments. Cytokine release was measured by cytometric bead array...

Hypertension in obese Zucker rats is associated with raised plasma aldosterone, suppressed renin and increased hypothalamo–pituitary–adrenal activity. We investigated the possible causes and consequences of these associations by comparing adrenal gene expression and urinary electrolyte and steroid excretion patterns in lean and obese rats. Groups (n=11) of adult male lean and obese Zucker rats were held in metabolism cages for 7 days. Urine collected over the ...

Glucocorticoid metabolism is altered in a tissue-specific manner in obesity. Increased reactivation of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1) amplifies glucocorticoid action in abdominal fat, whereas increased metabolism of glucocorticoids by hepatic A-ring reductases may contribute to activation of the hypothalamic-pituitary-adrenal axis. These changes have been characterised in leptin-resistant obese Zucker rats and obese humans. Here we inves...

Metabolism of glucocorticoids to dihydro and tetrahydro derivatives via hepatic 5alpha- and 5beta-reductases has been assumed to be a pathway of irreversible inactivation of glucocorticoids. However, 5alpha-reduced metabolites of other steroids (testosterone, aldosterone) have significant affinity for the parent hormone receptor. We have investigated whether 5alpha-reduced metabolites of corticosterone (B) are GR agonists.In hepatocytes from male lean Zucker rats (n=6) com...

5beta-Reductase is a key glucocorticoid metabolising enzyme. In humans, urinary steroid metabolite profiles suggest an inverse relationship between 5beta-reductase and 11beta-hydroxysteroid dehydrogenase (11HSD1) in obesity and congenital deficiency of 11HSDs. Indeed in the obese Zucker rat hepatic 11HSD1 is decreased and 5beta-reductase increased. Here we use animal models with well characterised alterations in 11HSD1 to explore the link between these enzymes.11HSD1 was m...