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A novel selective 11b-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis.

Bujalska, I.J and Gathercole, L.L and Tomlinson, J W and Darimont, C and Ermolieff, J and Fanjul, A.N and Rejto, P.A and Stewart, P M (2008) A novel selective 11b-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis. Journal of Endocrinology, 197. pp. 297-307. ISSN 0022-0795

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URL of Published Version: http://joe.endocrinology-journals.org/cgi/reprint/197/2/297.pdf

Identification Number/DOI: DOI: 10.1677/JOE-08-0050

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, 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) activates cortisol from cortisone locally within adipose tissue, and inhibition of 11b-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 11b-HSD1 in regulating adipose tissue differentiation. Human cells were differentiated with 1.0 mM cortisol (F), or cortisone (E) with or without 100 nM of a highly selective 11b-HSD1 inhibitor PF-877423. 11b-HSD1 mRNA expression increased across adipocyte differentiation (P!0.001, nZ4), which was paralleled by an increase in 11b-HSD1 oxo-reductase activity (from nil on day 0 to 5.9G1.9 pmol/mg per h on day 16,P!0.01, nZ7). 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-incubation 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 11b-HSD1 mRNA expression and activity is essential for the induction of human adipogenesis. Blocking adipogenesis with a novel and specific 11b-HSD1 inhibitor may represent a novel approach to treat obesity in patients with MS.

Type of Work:Article
Date:04 March 2008 (Publication)
School/Faculty:Schools (1998 to 2008) > School of Medicine
Department:Division of Medical Sciences
Subjects:R Medicine (General)
Institution:University of Birmingham
Copyright Holders:Society for Endocrinology
ID Code:119
Refereed:YES
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