Endocrine Abstracts

In humans, glucocorticoids (GC) are implicated in the pathogenesis of obesity and insulin resistance. In adipose tissue, GCs are regulated at the prereceptor level by oxo-reductase activity of 11beta-hydroxysteroid dehydrogenases type 1 (11β-HSD1). The hexose-6-phosphate dehydrogenase null mouse (H6PDH/KO) has shown that H6PDH is required for generating NADPH within the endoplasmic reticulum which determines the direction of 11β-HSD1 enzyme. We have shown that mRNA for 11β-HSD1, H6PDH and the glucocorticoid receptor are expressed in murine adipose tissue depots. This was confirmed at protein levels for 11β-HSD1 and H6PDH by western blotting. H6PDH/KO mice despite having equal amounts of 11β-HSD1, show a change in enzyme set-point from oxo-reductase in WT (218.5±55.4 pmol/mg/h (gonadal fat (GF) explants); 25.3±18.7 pmol/mg/h (GF preadipocytes) mean±S.D., P<0.001) to dehydrogenase in H6PDH/KO mice (300.2±28.7 pmol/g wet tissue/h (GF explants); 51.1±13.7 pmol/mg/h (GF preadipocytes), P<0.001). The H6PDH/KO mice are smaller (26.9±3.1 g vs 32.7±5.3 g, mean±S.D., P=0.006) and have smaller fat pads (KO: 0.49±0.19, 0.18±0.13; WT 0.89±0.54, 0.24±0.2, gram, mean±S.D.; GF and perirenal fat (PrF) respectively), but they are proportional to their body weight (BW) (GF/BW%: 2.6%±0.1.2 (WT); 1.8%±0.6 (H6PD/KO), mean±S.D.; and PrF/BW%: 0.7±0.5 (WT); 0.7±0.4 (H6PD/KO)). However, histological examination revealed that there was no difference in the average adipocyte size between WT and H6PDH/KO mice. Analysis using Affymetrix arrays from H6PDH/KO GF showed decreased expression of genes involved in lipogenesis; glycerol 3-phosphate dehydrogenase and PI3 kinase (2.6 and 2.1 respectively) and lipolysis (adiponutrin, 2.1-fold), indicating altered rates of fat metabolism in H6PDH/KO mice. We conclude that the change in set point of 11β-HSD1 due to the absence of H6PDH alters adipose tissue metabolism possibly by inhibition of both lipolysis and lipogenesis.