Endocrine Abstracts

In humans, glucocorticoids (GC) are implicated in the pathogenesis of obesity and insulin resistance. GCs are regulated at the prereceptor level by 11beta-hydroxysteroid dehydrogenases (11β-HSD). 11β-HSD type 1 (11β-HSD1) predominantly displays oxo-reductase activity, converting cortisone in man, 11-dehydrocorticosterone in rodents, to cortisol and corticosterone respectively – a reaction requiring the cofactor NADPH. The generation of a hexose-6-phosphate ...

The adrenal steroid dehydroepiandrosterone (DHEA) has been shown in vivo, to mimic the effects of peroxosome proliferator-activated receptor (PPAR) ligands and oppose those of glucocorticoids, thus producing beneficial effects on insulin sensitivity and adipogenesis in obese and diabetic rodents. Furthermore, DHEA treatment has recently been shown to reduce subcutaneous and visceral fat in humans in vivo. However, the mechanism by which DHEA produces these anti-a...

The pathological effects of glucocorticoids (GC) are exemplified by patients with Cushing’s syndrome who develop central obesity, insulin resistance and in some cases, type 2 diabetes mellitus. It is generally accepted that GC cause insulin resistance, however, both insulin and GC increase adipocyte differentiation. The question therefore arises as to how GC stimulate adipocyte differentiation whilst apparently making adipocytes insulin resistant. We have hypothesized tha...

The prevalence of obesity and its association with many health complications have evoked a high interest in adipose tissue metabolism. In man, glucocorticoid (GC) excess increases fat mass and the risk of developing Metabolic Syndrome. The enzyme responsible for modifying intracellular GC concentrations in adipose tissue is 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The aim of this study was to characterise the novel human preadipocyte cell line (Chub-S7) an...

Glucocorticoid excess, Cushing's syndrome, is a recognised cause of insulin resistance and in some cases diabetes mellitus. In addition, patients develop reversible central obesity. However, the exact mechanisms that underpin the development of glucocorticoid mediated insulin resistance and central obesity are not known. We have hypothesized that at a cellular level, the tissue specific generation of cortisol from inactive cortisone through the action of 11beta-hydroxysteroid ...

Prostanoids have been elucidated as potent adipogenic hormones. Cyclooxygenase (PTGS) is the rate-limiting enzyme of prostanoid biosynthesis and its product, prostaglandin (PG) H2 is a precursor of PGE2, PGF2, PGD2 and PGI2. PGH2 is also metabolised by prostaglandin D-synthase (PTGDS) to PGD2 which spontaneously converts to PGJ2 or can be enzymatically converted to PGF2alpha by AKR1C3. These two metabolites have opposite effect on adipogenesis; PGF2alpha is a PPARgamma antagon...

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3) is a potent antiproliferative agent with putative applications in the treatment of common cancers. However, doses of 1,25D3 required to achieve tangible anticancer responses also stimulate unwanted calciotropic effects. Data suggest that this is due, in part, to acquired resistance to 1,25D3 in cancer cells, particularly in more aggressive tumours. To investigate this fu...

Glucocorticoids are an important adipogenic factor. In man, circulating cortisol excess causes visceral obesity, but in simple obesity glucocorticoid levels are usually normal. However, in adipose tissue cortisol availability to bind to the glucocorticoid receptor (GR) is modulated by 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1). Human preadipocytes display both dehydrogenase (cortisol to cortisone) and oxo-reductase (cortisone to cortisol) activity. Recent genet...

Glucocorticoids (GCs) mediate many of their physiological effects through inhibition of cell proliferation. More contentious is the antiproliferative action of GCs and their possible tumour-modifying effects in neoplastic tissues. However, in recent studies we have shown that 'prereceptor' metabolism of GCs by the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) is a pivotal determinant of cell proliferation and tumour formation. Two isozymes of 11beta-HSD interconvert ...

Patients with Cushing's syndrome develop florid, but reversible central obesity. However, circulating cortisol levels are not elevated in simple obesity. Within human adipose tissue, the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is highly expressed and converts inactive glucocorticoid, cortisone to active cortisol. Rodents over-expressing 11beta-HSD1 in adipocytes develop central obesity exclusively as a result of increased adipocyte size. Whilst it has ...