Endocrine Abstracts

Intra-abdominal adiposity is associated with insulin resistance and increased cardiovascular morbidity and mortality. Differences in gene expression between omental (om) and subcutaneous (sc) adipose have been described, but molecular mechanisms underpinning differences in adipose biology are not known. Patients with glucocorticoid excess, Cushing’s syndrome, develop a phenotype characterized by central obesity. We have characterized the regulation of lipogenesis by gluco...

Glucocorticoid (GC) excess (Cushing’s syndrome) is characterized by central obesity, insulin resistance and in up to 20% of cases, non-alcoholic fatty liver disease (NAFLD). NAFLD is a progressive spectrum of disease ranging from hepatic steatosis to steatohepatitis, fibrosis and cirrhosis. Many processes contribute to lipid accumulation within heaptocytes including de novo lipogenesis which includes the rate-limiting carboxylation of acetyl CoA to malonyl-CoA by a...

Glucocorticoid (GC) production rates are elevated in obese, insulin resistant individuals. We and others have demonstrated decreased hepatic cortisol regeneration through reduced 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity that converts inactive cortisone to cortisol. In addition, there is enhanced cortisol clearance by A-ring reductases, (notably 5α-reductase). We have argued that these changes drive the hypothalamo-pituitary–adrenal axis a...

Patients with glucocorticoid excess develop a phenotype characterized by central obesity, however, the impact of glucocorticoids upon the processes that regulate lipid accumulation has not been fully explored. We hypothesize that intracellular generation of cortisol from cortisone by 11b-hydroxysteroid dehydrogenase type 1 (11bHSD1) is an important regulator of lipid metabolism.In adipocytes, acetyl-CoA carboxylase 1 and 2 (ACC1/2) convert acetyl-CoA to ...

Non alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. The potential role of glucocorticoids (GC) in the pathogenesis of NAFLD, is highlighted by patients with GC excess, Cushing’s syndrome, who develop central adiposity, insulin resistance and in 20% of cases, NAFLD. Although in most cases of NAFLD, circulating cortisol levels are normal, hepatic cortisol availability is controlled by enzymes that regenerate cortisol from inacti...

The role of endogenous glucocorticoid (GC) production and metabolism in the pathogenesis of obesity, insulin resistance and type 2 diabetes remains unclear. Patients with Cushing’s syndrome develop central obesity, insulin resistance and in some cases type 2 diabetes (T2DM), yet circulating cortisol levels are not elevated in simple obesity. Alterations in GC metabolism, including 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that generates active cortisol ...

Glucocorticoid (GC) excess is characterized by increased adiposity, skeletal myopathy and insulin resistance. Despite the increasing use of GCs as therapeutic agents, the molecular mechanisms that underpin GC mediated changes in insulin signalling are not clear. Within skeletal muscle, the microsomal enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive GC, 11-dehydrocorticosterone (A) to active corticosterone (B) and thus regulates GC availabi...

Glucocorticoid (GC) excess is characterized by increased adiposity, skeletal myopathy and insulin resistance. Despite the increasing use of GCs as therapeutic agents, the molecular mechanisms that underpin the GC mediated changes in insulin signalling are not clear. The majority of previous studies have used rodent models and have shown regulation at the level of the insulin receptor (IR), IRS-1 and PI3 kinase.Primary cultures of human skeletal myocytes ...

Thyroid hormone resistance (THR) is associated with elevated FT4 and FT3 with inappropriately high TSH levels. T3 action is mediated by two types of thyroid hormone receptor, encoded by alpha and beta genes. We evaluated the endothelial function of a THR transgenic mouse model with a targeted mutation in the thyroid hormone beta receptor gene ex vivo.Isometric tension of aortic rings of 10 mice of each genotype (TRbPV/PV, TRbPV/+</...

A role for local corticosteroid metabolism by 11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) has been proposed in bone and adipose tissue physiology. In vivo, 11b-HSD1 predominantly converts inactive cortisone to active cortisol and enzyme activity is critically dependent on substrate concentration. To examine 11b-HSD1 activity in vivo we have analysed the relationship between serum cortisone and markers of bone turnover, BMD and adipose tissue mass in a c...