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J. Biol. Chem., Vol. 282, Issue 15, 11038-11046, April 13, 2007

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Differential Modulation of 3T3-L1 Adipogenesis Mediated by 11-Hydroxysteroid Dehydrogenase-1 Levels^*

From the Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, and the Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, Illinois 60637

The localized activation of circulating glucocorticoids in vivo by the enzyme 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) plays a critical role in the development of the metabolic syndrome. However, the precise contribution of 11-HSD1 in the initiation of adipogenesis by inactive glucocorticoids is not fully understood. 3T3-L1 fibroblasts can be terminally differentiated to mature adipocytes in a glucocorticoid-dependent manner. Both inactive rodent dehydrocorticosterone and human cortisone were able to substitute for the synthetic glucocorticoid dexamethasone in 3T3-L1 adipogenesis, suggesting a potential role for 11-HSD1 in these effects. Differentiation of 3T3-L1 cells caused a strong increase in 11-HSD1 protein levels, which occurred late in the differentiation protocol. Reduction of 11-HSD1 activity in 3T3-L1 fibroblasts, achieved by pharmacological inhibition or adenovirally mediated delivery of short hairpin RNA constructs, specifically blocked the ability of inactive glucocorticoids to drive 3T3-L1 differentiation. However, even modest increases in exogenous 11-HSD1 expression in 3T3-L1 fibroblasts, to levels comparable with endogenous 11-HSD1 in differentiated 3T3-L1 adipocytes, were sufficient to block adipogenesis. Luciferase reporter assays indicated that overexpressed 11-HSD1 was catalyzing the inactivating dehydrogenase reaction, because the ability of both active and inactive glucocorticoids to activate the glucocorticoid receptor were largely suppressed. These results suggest that the temporal regulation of 11-HSD1 expression is tightly controlled in 3T3-L1 cells, so as to mediate the initiation of differentiation by inactive glucocorticoids and also to prevent the inhibitory activity of prematurely expressed 11-HSD1 during adipogenesis.

Received for publication, June 28, 2006 , and in revised form, February 20, 2007.

^* This work was supported in part by Pilot and Feasibility Grant P60DK020595 from the Diabetes Research and Training Center at the University of Chicago (to J. K.) and Training Grant T32HL007909 (to K. A. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

This paper is dedicated to the memory of Dr. Jaime Kim (1972–2005).

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: MC1027, 5841 S. Maryland Ave., Chicago, IL 60637. Tel.: 773-702-2346; Fax: 773-834-0486; E-Mail: mbrady{at}medicine.bsd.uchicago.edu.

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