This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Balachandran, A. Articles by Yang, K. Search for Related Content PubMed PubMed Citation Articles by Balachandran, A. Articles by Yang, K.

Insulin and Dexamethasone Dynamically Regulate Adipocyte 11β-Hydroxysteroid Dehydrogenase Type 1

Children’s Health Research Institute and Lawson Health Research Institute (A.B., H.G., M.S., K.Y.), Departments of Obstetrics and Gynaecology and Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada N6A 4G5; and Lawson Health Research Institute (S.U.), Department of Medicine, University of Western Ontario, London, Ontario, Canada N6A 4V2

Address all correspondence and requests for reprints to: Dr. K. Yang, Children’s Health Research Institute, Room A5-132, Victoria Research Laboratories Westminster Campus, 800 Commissioners Road East, London, Ontario, Canada N6A 4G5. E-mail: kyang{at}uwo.ca.

The adipocyte enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies local glucocorticoid action by generating active glucocorticoids from inactive metabolites and has emerged as a key player in the pathogenesis of central obesity and metabolic syndrome. However, the regulation of adipocyte 11β-HSD1 is incompletely understood. Therefore, the present study was designed to investigate the effects of insulin and glucocorticoid as well as their underlying molecular mechanisms on 11β-HSD1 activity and expression in 3T3-L1 adipocytes and determine whether the in vitro findings could be confirmed in vivo. Our main in vitro findings are 1) insulin stimulated whereas dexamethasone inhibited 11β-HSD1 activity and expression in a time- and concentration-dependent manner; 2) the effect of dexamethasone was mimicked by both cortisol and corticosterone but blocked by the glucocorticoid receptor antagonist RU486; 3) the p38 MAPK inhibitor SB220025, but not the ERK inhibitor U0126 or the phosphatidylinositol 3-kinase inhibitor LY294002, prevented insulin stimulation of 11β-HSD1 activity; and 4) although dexamethasone did not alter the half-life of 11β-HSD1 mRNA, insulin doubled it. Taken together, these in vitro results demonstrate that insulin stimulates adipocyte 11β-HSD1 through a posttranscriptional mechanism that involves activation of the p38 MAPK signaling pathway, whereas dexamethasone exerts an opposite effect by a glucocorticoid receptor-mediated transcriptional mechanism. In contrast, both insulin and dexamethasone augmented 11β-HSD1 activity and expression in rat white adipose tissue in vivo, thus confirming the role of insulin but revealing a fundamental difference regarding the role of dexamethasone in regulating adipocyte 11β-HSD1 between the two model systems.

This article has been cited by other articles:

				I. D. Ignatova, R. M. Kostadinova, C. E. Goldring, A. R. Nawrocki, F. J. Frey, and B. M. Frey Tumor necrosis factor-{alpha} upregulates 11{beta}-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-{beta} in HepG2 cells Am J Physiol Endocrinol Metab, February 1, 2009; 296(2): E367 - E377. [Abstract] [Full Text] [PDF]