Local glucocorticoids action depends on 11β hydroxysteroid dehydrogenase (11β-HSD) enzymes. Adipose tissues mainly express the 11β-HSD1, which activates inactive cortisone. Altered 11β-HSD1 and GLUT4 expressions have been reported in obesity. GLUT4 participates in the genesis and maintenance of insulin resistance/obesity, and could also be involved in the insulin resistant state observed in hypercortisolism. The aim of this study was to investigate the 11β-HSD1 and GLUT4 expressions in visceral (VAT) and subcutaneous (SAT) adipose tissues of insulin resistant, hypercorticosteronemic MSG-obese rats, considering the tissue-specific action of glucocorticoids.
Methods: Male Wistar rats (C) were rendered obese (O), by neonatal treatment with monosodium glutamate (4 mg/g per day). Insulin tolerance tests (ITT), plasma insulin and corticosterone confirmed the obesity features. GLUT4 and 11β-HSD1 mRNAs were analyzed in VAT and SAT, by northern blotting and RT-PCR respectively. Sterol regulatory element binding protein-1c (SREBP-1c) expression and binding activity were also investigated.
Results: Obese rats were hyperinsulinemic (O=61.4±5.0 μU/ml, P<0.05 vs C=40.1±5.5 μU/ml), hypercorticosteronemic (O=168.3±9.5 ng/ml P<0.001 vs C=80.3±9.8 ng/ml) and insulin resistant (kITT=3.42%/min, P<0.01 vs C: 5.06%/min). GLUT4 mRNA was decreased in obese VAT (O=80.9±3.8 UA, P<0.01 vs C=100.2±4.2 UA), where 11β-HSD1 mRNA was increased (O=142.5±6.9 UA, P<0.01 vs C=100.0±5.8 UA). On the contrary, in obese SAT GLUT4 mRNA was increased (O=122.1±9.4 UA, P<0.05 vs C=100.0±5.3 UA) while 11β-HSD1 was decreased (O=78.0±7.5 UA, P<0.05 vs C=100.0±5.2 UA). SREBP1-c binding activity to GLUT4 promoter sequence was unaltered. However, SREBP-1c expression was significantly lower in obese VAT (O=82.0±4.0 UA, P<0.05 vs C=100.0±4.4), remaining unchanged in obese SAT (O=94.8±3.2 UA, P<0.05 vs C=100.0±6.3 UA).
Conclusion: Data suggest an inhibitory effect of glucocorticoids on GLUT4 gene expression in VAT, determined by a higher expression of the 11β-HSD1 enzyme. This effect may involve mechanisms at transcriptional level, since the expression of SREBP1-c, a transcriptional factor known to increase GLUT4 gene transcription, was shown to be decreased in VAT. Financial support: 07/59722-4.
30 Apr - 04 May 2011
European Society of Endocrinology