Endocrine Abstracts

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), regenerates active glucocorticoids (cortisol, corticosterone) from inert substrates (cortisone, 11-dehydrocorticosterone) and has been implicated in the pathogenesis of the metabolic syndrome. 11β-HSD1 expression is increased in adipose tissue and decreased in liver in human and rodent obesity. Paradoxically, in chronically high fat-fed mice 11β-HSD1 is down-regulated in adipose tissue. Transcription of 11β-HSD1 is directly enhanced by CCAAT/enhancer binding protein C/EBPα, whereas C/EBPβ attenuates this action. Therefore, the cellular ratio of C/EBP isoforms may be an important determinant of the level of 11β-HSD1 transcription. Here, we investigated how diet influences the expression of 11β-HSD1 and C/EBPs in liver and adipose tissue. Mice (10/group) were fed low fat (LF, 11% calories from fat) or high fat (HF, 58%) diet for 6 weeks. Levels of mRNA encoding 11β-HSD1, C/EBPα, β, δ and ζ, in liver and adipose tissue (subcutaneous and mesenteric) were measured by real-time PCR. 11β-HSD1 mRNA levels were lower in both liver (69.2±3.4% of LF control; P<0.001) and adipose tissue (22.9±2.7% and 32.8±4% of LF control in subcutaneous and mesenteric, respectively, P<0.001) of HF-fed mice. HF diet increased C/EBPδ (499.5±8.1%; P<0.001) and C/EBPζ (171.4±14.9%; P<0.001) mRNA levels in liver and subcutaneous adipose tissue, respectively, while the other C/EBPs were unchanged. In vitro, C/EBPβ, δ, and ζ antagonised C/EBPα activation of the 11β-HSD1 promoter. Therefore, increased C/EBPδ and ζ may mediate the suppression of 11β-HSD1 levels in liver and adipose in response to HF diet.