Insulin and dexamethasone dynamically regulate adipocyte 11beta-hydroxysteroid dehydrogenase type 1.
The adipocyte enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-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 11beta-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 11beta-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 11beta-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 11beta-HSD1 activity; and 4) although dexamethasone did not alter the half-life of 11beta-HSD1 mRNA, insulin doubled it. Taken together, these in vitro results demonstrate that insulin stimulates adipocyte 11beta-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 11beta-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 11beta-HSD1 between the two model systems.
Balachandran
Aran
A
Children's Health Research Institute and Lawson Health Research Institute, London, Ontario, Canada.
Guan
Haiyan
H
Sellan
Michael
M
van Uum
Stan
S
Yang
Kaiping
K
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics* / Q000378:metabolism; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D006727:Hormone Antagonists; D007328:Insulin; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D015735:Mifepristone; D003907:Dexamethasone; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1