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 genetic data in patients with cortisone reductase deficiency, suggest that hexose-6-phosphate dehydrogenase (H6PDH) generates NAPDH in the enoplasmic reticulum (ER) and permits 11 beta-HSD1 oxo-reductase activity. Using Dicer technology (GeneTherapy, US), siRNA 22bp oligos against H6PDH were transfected into HEK 293T1 cells (a stably transfected cell line over-expressing 11 beta-HSD1). Using real-time PCR, 72h post-transfection, H6PDH mRNA expression decreased by 38.5%±5.7 (mean±SE, n=3). 11b-HSD1 reductase activity decreased by 12.0%±0.48 (mean±SE, n=3) and dehydrogenase activity increased by 21.2±0.8 (mean±SE, n=3). There was no change in 11 beta-HSD1 mRNA expression. To determine whether these observations extended to the clinical setting, H6PDH expression and 11b-HSD1 reductase activity were determined in 15 omental preadipocyte cultures obtained at elective surgery. When divided according to 11 beta-HSD1 activity (above and below the median value, H6PDH mRNA expression was 1.9 fold higher in those cell with the highest 11 beta-HSD1 activity (dCt: 10.7±0.2 vs. 11.6±0.3, p<0.05). Conversely, there was no difference in 11 beta-HSD1 mRNA expression between the high and low activity cultures (dCt: 12.1±0.4 vs. 12.6±0.3, p=0.3). In addition, whilst 11 beta-HSD1 reductase activity decreased with BMI, without an alteration in 11 beta-HSD1 mRNA expression, H6PDH expression showed a significant inverse correlation with BMI (p<0.05). This study, confirms a direct functional link between 11 beta-HSD1 oxo-reductase activity and H6PDH. H6PDH induces 11 beta-HSD1 oxo-reductase activity and may be the key factor underpinning the association of 11 beta-HSD1 with hepatic glucose output and visceral adiposity. As such it offers the possibility of a further novel therapeutic target.
22 - 24 Mar 2004
British Endocrine Societies