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Suppression of 11β-hydroxysteroid dehydrogenase type 1 with RNA interference substantially attenuates 3T3-L1 adipogenesis

¹ Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
² Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
³ Department of Kidney Disease Center, Medical College of Wisconsin, Milwaukee, Wisconsin
⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regulates the local level of glucocorticoids, has been suggested to be involved in the development of obesity. A definitive functional role for 11β-HSD1 in adipogenesis, however, remains to be established. We developed 3T3-L1 cell lines stably transfected with a small hairpin RNA (shRNA) targeting 11β-HSD1. A shRNA containing two nucleotide substitutions was used as a control. Silencing of 11β-HSD1 substantially attenuated the accumulation of lipid droplets and the expression of adipogenesis marker genes, which was induced by a mixture containing either corticosterone or dexamethasone. Silencing of 11β-HSD1 increased the concentration of 11-dehydrocorticosterone in the culture supernatant but did not significantly affect the levels of corticosterone or dexamethasone. Translocation of glucocorticoid receptors to the nucleus in response to glucocorticoids was significantly attenuated by silencing 11β-HSD1. The number of cells entering the S phase of the cell cycle following the induction of adipogenesis was significantly reduced by silencing 11β-HSD1. 11β-HSD1 shRNA delivered by lentiviral vectors after the induction of differentiation, however, did not affect the progression of adipogenesis. These results indicate that 11β-HSD1 plays a significant functional role in the initiation of 3T3-L1 adipogenesis and provide new mechanistic insights into the role of 11β-HSD1 in the development of obesity and related diseases.

obesity; metabolic syndrome; glucocorticoids; cell cycle; small interfering RNA

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