Regulation of expression of 11 beta-hydroxysteroid dehydrogenase type 1 inadipose tissue: Tissue-specific induction by cytokines

Patients with glucocorticoid excess develop central obesity, yet in simple obesity, circulating glucocorticoid levels are normal. We have suggested th at the increased activity and expression of the enzyme 11 beta -hydroxyster oid dehydrogenase type 1 (11 beta HSD1) generating active cortisol from cor tisone within adipose tissue may be crucial in the pathogenesis of obesity. In this study primary cultures of human hepatocytes and adipose stromal ce lls (ASC) were used as in vitro models to investigate the tissue-specific r egulation of 11 beta HSD1 expression and activity. Treatment with tumor necrosis factor-alpha (TNF alpha) caused a dose-depend ent increase in 11 beta HSD1 activity in primary cultures of both sc [1743. 1 +/- 1015.4% (TNF alpha, 10 ng/ml); P < 0.05 vs. control (100%)] and oment al [375.8 +/- 57.0% (TNF alpha, 10 ng/ml); P < 0.01 vs. control (100%)] ASC , but had no effect on activity in human hepatocytes [90.2 +/- 2.8% (TNF al pha, 10 ng/ml); P = NS vs, control (100%)]. Insulin-like growth factor I (I GF-I) caused a dose-dependent inhibition of 11 beta HSD1 activity in sc [49 .7 +/- 15.0% (IGF-I, 100 ng/ml]; P < 0.05 vs. control (100%)] and omental [ 71.6 +/- 7.5 (IGF-I, 100 ng/ml); P < 0.01 us. control (100%)] stromal cells , but not in human hepatocytes [101.8 +/- 15.7% (IGF-I, 100 ng/ml); P = NS vs, control (100%)]. Leptin treatment did not alter 11 beta HSD1 activity i n human hepatocytes, but increased activity in omental ASC [135.8 +/- 14.1% aeptin, 100 ng/ml); P = 0.08 vs, control (100%)]. Treatment with interleuk in-1 beta induced 11 beta HSD1 activity and expression in sc and omental. A SC in a time-and dose-dependent manner. 15-Deoxy-Delta 12,14-PGJ2, the puta tive endogenous ligand of the orphan nuclear receptor peroxisome proliferat or-gamma, significantly increased 11 beta HSD1 activity in omental cells [1 79.7 +/- 29.6% (1 muM); P < 0.05 vs. control (100%)] and sc [185.3 +/- 12.6 % (1 muM); P < 0.01 vs, control (100%)] ASC, and it is possible that expres sion of this ligand may ensure continued cortisol generation to permit adip ocyte differentiation. Protease inhibitors used in the treatment of human i mmunodeficiency virus infection are known to cause a lipodystrophic syndrom e and central obesity, but saquinavir, indinavir, and neflinavir caused a d ose-dependent inhibition of 11 beta HSD1 activity in primary cultures of hu man omental ASC. 11 beta HSD1 expression is increased in human adipose tissue by TNF alpha, interleukin-1 beta, leptin, and orphan nuclear receptor peroxisome prolifer ator-gamma agonists, but is inhibited by IGF-I. This autocrine and/or parac rine regulation is tissue specific and explains recent clinical data and an imal studies evaluating cortisol metabolism in obesity. Tissue-specific 11 beta HSD1 regulation offers the potential for selective enzyme inhibition w ithin adipose tissue as a novel therapy for visceral obesity.