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Ceramide and Adenosine 5'-Monophosphate-Activated Protein Kinase Are Two Novel Regulators of 11β-Hydroxysteroid Dehydrogenase Type 1 Expression and Activity in Cultured Preadipocytes

Division of Endocrinology and Metabolism (N.A., H.M., T.Ta., T.I., S.Y., N.K., T.To., M.N., T.K., J.F., K.E., M.H., K.H., K.N.), Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Department of Human Coexistence (T.H.), Kyoto University Graduate School of Human and Environmental Studies, Kyoto 606-8501, Japan; Department of Internal Medicine (H.S.), Osaka Dental University, Osaka 573-1121, Japan; and Department of Developmental Physiology (Y.M.), National Institute for Physiological Science, Aichi 444-8585, Japan

Address all correspondence and requests for reprints to: Hiroaki Masuzaki, M.D., Ph.D., Division of Endocrinology and Metabolism, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54, Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: hiroaki{at}kuhp.kyoto-u.ac.jp.

Increased activity of intracellular glucocorticoid reactivating enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in obese adipose tissue contributes to adipose dysfunction. As recent studies have highlighted a potential role of preadipocytes in adipose dysfunction, we tested the hypothesis that a variety of metabolic stress mediated by ceramide or AMP-activated protein kinase (AMPK) would regulate 11β-HSD1 in preadipocytes. The present study is the first to show that 1) expression of 11β-HSD1 in 3T3-L1 preadipocytes was robustly induced when cells were treated with cell-permeable ceramide analogue C₂ ceramide, bacterial sphingomyelinase, and sphingosine 1-phosphate, 2) 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)-induced activation of AMPK augmented the expression and enzyme activity of 11β-HSD1, and 3) these results were reproduced in human preadipocytes. We demonstrate for the first time that C₂ ceramide and AICAR markedly induced the expression of CCAAT/enhancer-binding protein (C/EBP) β and its binding to 11β-HSD1 promoter. Transient knockdown of C/EBPβ protein by small interfering RNA markedly attenuated the expression of 11β-HSD1 induced by C₂ ceramide or AICAR. The present study provides novel evidence that ceramide- and AMPK-mediated signaling pathways augment the expression and activity of 11β-HSD1 in preadipocytes by way of C/EBPβ, thereby highlighting a novel, metabolic stress-related regulation of 11β-HSD1 in a cell-specific manner.