Cushings syndrome is characterized by a diverse set of clinical manifestations, including hypertension, apparent obesity and metabolic aberrations such as diabetes, dyslipidaemia, ultimately leading to the metabolic syndrome. AMP-activated protein kinase (AMPK) is an intracellular energy sensor. It integrates nutritional and hormonal signals by switching on catabolic pathways, such as fatty acid oxidation and glycolysis and switching off anabolic pathways, such as fatty acid and protein synthesis. We have shown, in a well-established rat model of glucocorticoid excess, that AMPK activity in mesenteric fat was significantly reduced compared to controls (54±17%, P<0.05). We hypothesized that glucocorticoids (GR) can influence the expression of the genes involved in lipogenesis and this effect could be at least partly via AMPK.
Rats were implanted with corticosterone- or cholesterol (placebo)-containing pellets, and both groups consumed chow and 30% sucrose ad libitum for two weeks. Gene expression in mesenteric fat tissue was analyzed by reverse transcription followed by real time quantitative PCR with primers specific for phosphoenolpyruvate carboxykinase (PECPK), sterol regulatory element-binding protein-1c (SREBP1c), fatty acid synthase (FAS), ampkα1 and ampkα2. β-actin was used as housekeeping gene.
GR increased PEPCK mRNA expression and this was significantly higher than in the control group (5.5±2.38 vs 2.6±0.9, P=0.01). There was also a trend to an increase for SREBP1c levels (14.5±5.7 vs 9.9±2.4, P=0.07), but not for FAS (34.8±14.4 vs 28.4±12.4, P=0.43). The expression of ampkα1 and ampkα2 mRNA was similar in the two groups, with ampkα1 being the predominant form on this tissue.
We demonstrate that glucocorticoids, in agreement with the lower AMPK activity, could influence glyceroneogenesis via PEPCK and lipogenesis via SREBP1c in mesenteric adipose tissue. Whether this effect is due only to a direct effect of the GR on transcriptional regulation of PEPCK and SREBP1c or it is also due to AMPK inhibition by GR is a question of future research.
06 - 07 Nov 2006
Society for Endocrinology