Peroxisome Proliferator-activated Receptor-γ Ligands Inhibit Adipocyte 11β-Hydroxysteroid Dehydrogenase Type 1 Expression and Activity

Peroxisome proliferator-activated receptor- gamma (PPAR gamma ) has been shown to play an important role in the regulation of expression of a subclass of adipocyte genes and to serve as the molecular target of the thiazolidinedione (TZD) and certain non-TZD antidiabetic agents. Hypercorticosteroidism leads to insulin resistance, a variety of metabolic dysfunctions typically seen in diabetes, and hypertrophy of visceral adipose tissue. In adipocytes, the enzyme 11 beta -hydroxysteroid dehydrogenase type 1 (11 beta -HSD- 1) converts inactive cortisone into the active glucocorticoid cortisol and thereby plays an important role in regulating the actions of corticosteroids in adipose tissue. Here, we show that both TZD and non-TZD PPAR gamma agonists markedly reduced 11 beta -HSD-1 gene expression in 3T3-L1 adipocytes. This diminution correlated with a significant decrease in the ability of the adipocytes to convert cortisone to cortisol. The half-maximal inhibition of 11 beta -HSD-1 mRNA expression by the TZD, rosiglitazone, occurred at a concentration that was similar to its K sub(d) for binding PPAR gamma and EC sub(50) for inducing adipocyte differentiation thereby indicating that this action was PPAR gamma -dependent. The time required for the inhibitory action of the TZD was markedly greater for 11 beta -HSD-1 gene expression than for leptin, suggesting that these genes may be down-regulated by different molecular mechanisms. Furthermore, whereas regulation of PPAR gamma -inducible genes such as phosphoenolpyruvate carboxykinase was maintained when cellular protein synthesis was abrogated, PPAR gamma agonist inhibition of 11 beta -HSD- 1 and leptin gene expression was ablated, thereby supporting the conclusion that PPAR gamma affects the down-regulation of 11 beta -HSD-1 indirectly. Finally, treatment of diabetic db/db mice with rosiglitazone inhibited expression of 11 beta -HSD-1 in adipose tissue. This decrease in enzyme expression correlated with a significant decline in plasma corticosterone levels. In sum, these data indicate that some of the beneficial effects of PPAR gamma antidiabetic agents may result, at least in part, from the down-regulation of 11 beta -HSD-1 expression in adipose tissue.