Endocrine Abstracts

Background: The detrimental effect of excessive obesity on insulin resistance has been well established. The expansion of adipose tissue is closely dependent on two processes: adipogenesis and angiogenesis and the Wnt signalling pathway has been reported to affect both. In adipose tissue the Wnt signalling pathway functions in a converse manner: increasing commitment of mesenchymal stem cells to preadipocytes and inhibiting differentiation of preadipocytes to mature adipocytes...

Nearly all the functions of the liver display zonation in distribution within each the lobule. Hepatic cortisol availability is controlled by enzymes that regenerate cortisol from inactive cortisone (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1). Dysregulation of hepatic 11β-HSD1 activity has been implicated in insulin resistance. Key processes such as gluconeogenesis are located in the periportal hepatocytes, although current dogma describes hepatic 11&#94...

Human studies indicate that local glucocorticoid (GC) generation within osteoblasts plays a critical role in various bone diseases. Human osteoblasts express the enzyme 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) that converts inactive GCs (cortisone, dehydrocorticosterone) to their active counterparts (cortisol, corticosterone). This activation capacity critically depends on expression of a cofactor generating enzyme hexose-6-phosphate dehydrogenase. Enzyme expression ...

It is well established that the use of therapeutic glucocorticoids to treat inflammatory disease has detrimental effects on bone and we have proposed that these clinical effects are determined by intracellular glucocorticoid generation (inactive cortisone/prednisone to cortisol/prednisolone) by 11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1). We have recently shown that glucocorticoids and cytokines are able to act cooperatively to upregulate the action of 11b-HSD1, a fi...

Therapeutic glucocorticoids are used in rheumatoid arthritis (RA) to reduce inflammation and bone destruction. We recently reported that primary synovial fibroblasts generate active glucocorticoids via expression of 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme activates cortisol from inactive cortisone (and prednisolone from prednisone) and this activity is up-regulated by inflammation. We have now examined glucocorticoid metabolism in synovial tissu...

In humans glucocorticoid (GC) excess can promote hepatic glucose and triglyceride production contributing to obesity, fatty liver and diabetes. 11β-HSD1 activates GCs (11-DHC to corticosterone in mice), thereby increasing tissue concentrations. The liver has the highest 11β-HSD1 activity, and its inhibition has emerged as a therapeutic option. To investigate this we generated 11β-HSD1 liver-specific knockouts (HSD1LKO) and examined GC metabolism and responses to...

Synovial fibroblasts (SFs) form a substantial component of inflamed rheumatoid synovium and generate endogenous glucocorticoids (GCs) during inflammation. Recently, production of DKK-1 (a Wnt signalling inhibitor that reduces bone formation) by SFs in response to TNFα has been proposed to be the master regulator of inflammatory osteoporosis. We have identified that in addition to TNFα, GCs potently induce DKK-1 secretion. This may provide a novel mechanism whereby lo...

High dose glucocorticoids are effective in suppressing inflammatory synovitis but have adverse effects on other connective tissues. In inflammatory arthritis glucocorticoids suppress the capacity of synovial fibroblasts (SFs) to recruit leukocytes to the joint whereas poor skin healing is due to impaired dermal fibroblast (DF) function. It is unknown whether these clinical differences are due to similar or distinct effects of glucocorticoids on fibroblast function.<p class...

The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme is a tissue specific regulator of glucocorticoid action that is linked to the development of osteoporosis, inflammatory arthritis and myopathy. Systemic inhibition of 11β-HSD1 enzyme activity has been proposed as a therapeutic option in these conditions. However, 11β-HSD1 activity has also been reported to be important in regulation of the immune response and the HPA axis. We have previously demo...