CCAAT/enhancer-binding proteins (C/EBPs) regulate the basal and cAMP-induced transcription of the human 11β-hydroxysteroid dehydrogenase encoding gene in adipose cells

Android obesity is often associated with a metabolic syndrome characterized, in particular, by a type 2 diabetes and cardiovascular problems. This could be induced by an excess of local production of glucocorticoids (GC) by adipose tissue (or other tissues). This production of GC by its target tissues depends on the 11 beta-hydroxysteroid dehydrogenase type I (11 beta HSD1) enzyme. Our aim was to characterize some mechanisms which control the expression of the human 11 beta HSD1 gene (hHSD11B1) in preadipocytes. By using different luciferase constructs containing fragments of the hHSD11B1 promoter, we demonstrate that two members of the CCAAT/enhancer-binding protein family, C/EBP alpha and C/EBP beta, are required for the basal transcriptional activity of HSD11B1 in 3T3-L1 preadipocyte cells. This effect depends on the binding of each isoform to specific binding sites. Mutation of either one of these sites induced a 40-50% decrease of the constitutive activity of the hHSD11B1 promoter. A forskolin treatment of 3T3-L1 preadipocyte cells induced an increased endogenous expression of HSD11B1. By transfection studies using the hHSD11B1 luciferase constructs, it appears that C/EBP beta was strongly involved in this induction, as the forskolin stimulation was suppressed after mutation of the C/EBP beta binding site. Part of the mechanism involved the increase of nuclear C/EBP beta protein levels induced by forskolin and a phosphorylation step associated with an enhanced binding of the transcription factor to its site. These data indicate that members of the C/EBP family control intracellular levels of GC in preadipocytes via the regulation of the constitutive and cAMP-dependent expressions of HSD11B1. (c) 2006 Elsevier SAS. All rights reserved.