Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2007) 13 P178

SFEBES2007 Poster Presentations Diabetes, metabolism and cardiovascular (63 abstracts)

Abnormalities in lipogenesis and lipolysis in Mice Lacking Hexose-6-Phosphate Dehydrogenase (H6PDH)

Kylie Hewitt 1 , Iwona Bujalska 1 , Gareth Lavery 1 , David Hauton 2 , Elizabeth Walker 1 & Paul Stewart 1


1Department of Medicine, Divison of Medical Sciences, University of Birmingham, Birmingham, United Kingdom; 2Department of Physiology, Division of Medical Sciences, University of Birmingam, Birmingham, United Kingdom.


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.

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