Endocrine Abstracts

Background: 11β-hydroxysteroid dehydrogenases (11β-HSD1&2) interconvert cortisol (F) and cortisone (E). Although 11β-HSD1 reductase activity has been measured in vivo, E production (dehydrogenase activity) has not been quantified using a Gold Standard technique, steady state tracer infusion.Aim: To develop a method to measure E production in vivo using the stable isotope tracer d2-cortisone (d2E).Me...

Glucocorticoids (cortisol in man, corticosterone in rodents) can inhibit angiogenesis, alter contractile function and reduce the inflammatory response to injury in the vascular wall. These effects are regulated by the 11beta-hydroxysteroid dehydrogenases (11HSDs) which inter-convert active glucocorticoids and their inactive 11-keto metabolites (cortisone; 11-dehydrocorticosterone) within target tissues. 11HSD2 is a unidirectional, exclusive dehydrogenase which inactivates gluc...

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...

Inhibiting 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1) has been proposed to prevent local regeneration of cortisol from cortisone, and thus enhance hepatic and adipose insulin sensitivity. In healthy men and patients with type 2 diabetes, the non-selective 11HSD inhibitor carbenoxolone enhances hepatic insulin sensitivity but, paradoxically, does not increase peripheral glucose disposal. In obesity, 11HSD1 activity and mRNA are increased in adipose biopsies. We tested ...

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...

Background: Kisspeptin is a neuropeptide central to the regulation of gonadotrophin secretion but recent studies have suggested more diverse roles in human physiology. Kisspeptin is a potent inhibitor of tumour metastasis and plays a role in placentation, both processes involving angiogenesis. In addition, Kisspeptin and its receptor, GPR54, have been identified in human blood vessels including aorta, coronary artery and umbilical vein, where they mediate vasoconstriction. We,...

Background: In mice, a methionine-choline deficient diet (MCDD) causes steatohepatitis and hepatic insulin resistance. In contrast, a simple choline-deficient diet (CDD) causes liver fat accumulation without steatohepatitis, insulin resistance or weight loss. We hypothesised that differences in liver and adipose fatty acid metabolism underlie the contrasting predisposition to steatohepatitis and hepatic insulin resistance.Methods: C57Bl6 mice (male, aged...

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...