Journal
JOURNAL OF ENDOCRINOLOGY
Volume 197, Issue 2, Pages 297-307Publisher
BIOSCIENTIFICA LTD
DOI: 10.1677/JOE-08-0050
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Funding
- Wellcome Trust [066357] Funding Source: Medline
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Glucocorticoid excess increases fat mass, preferentially within omental depots; yet circulating cortisol concentrations are normal in most patients with metabolic syndrome (MS). At a pre-receptor level, 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) activates cortisol from cortisone locally within adipose tissue, and inhibition of 11 beta-HSD1 in liver and adipose tissue has been proposed as a novel therapy to treat MS by reducing hepatic glucose output and adiposity. Using a transformed human subcutaneous preadipocyte cell line (Chub-S7) and human primary preadipocytes, we have defined the role of glucocorticoids and 11 beta-HSD1 in regulating adipose tissue differentiation. Human cells were differentiated with 1.0 mu M cortisol (F), or cortisone (E) with or without 100 nM of a highly selective 11 beta-HSD1 inhibitor PF-877423. 11 beta-HSD1 mRNA expression increased across adipocyte differentiation (P<0.001, n = 4), which was paralleled by an increase in 11 beta-HSD1 oxo-reductase activity (from nil on day 0 to 5.9 +/- 1.9 pmol/mg per h on day 16, P<0.01, n = 7). Cortisone enhanced adipocyte differentiation; fatty acid-binding protein 4 expression increased 312-fold (P<0.001) and glycerol-3-phosphate dehydrogenase 47-fold (P<0.001) versus controls. This was abolished by co-incubition with PF-877423. In addition, cellular lipid content decreased significantly. These findings were confirmed in the primary cultures of human Subcutaneous preadipocytes. The increase in 11 beta-HSD1 mRNA expression and activity is essential for the induction of human adipogenesis. Blocking adipogenesis with a novel and specific 11 beta-HSD1 inhibitor may represent a novel approach to treat obesity in patients with MS.
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