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Vol. 19, Issue 10, 4032-4041, October 2008

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Glucocorticoid Signaling Defines a Novel Commitment State during Adipogenesis In Vitro

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94107-2280

Submitted April 24, 2008; Revised July 3, 2008; Accepted July 10, 2008
Monitoring Editor: Kunxin Luo

Differentiation of 3T3-L1 preadipocytes can be induced by a 2-d treatment with a factor "cocktail" (DIM) containing the synthetic glucocorticoid dexamethasone (dex), insulin, the phosphodiesterase inhibitor methylisobutylxanthine (IBMX) and fetal bovine serum (FBS). We temporally uncoupled the activities of the four DIM components and found that treatment with dex for 48 h followed by IBMX treatment for 48 h was sufficient for adipogenesis, whereas treatment with IBMX followed by dex failed to induce significant differentiation. Similar results were obtained with C3H10T1/2 and primary mesenchymal stem cells. The 3T3-L1 adipocytes differentiated by sequential treatment with dex and IBMX displayed insulin sensitivity equivalent to DIM adipocytes, but had lower sensitivity to ISO-stimulated lipolysis and reduced triglyceride content. The nondifferentiating IBMX–then-dex treatment produced transient expression of adipogenic transcriptional regulatory factors C/EBPβ and C/EBP, and little induction of terminal differentiation factors C/EBP and PPAR. Moreover, the adipogenesis inhibitor preadipocyte factor-1 (Pref-1) was repressed by DIM or by dex-then-IBMX, but not by IBMX-then-dex treatment. We conclude that glucocorticoids drive preadipocytes to a novel intermediate cellular state, the dex-primed preadipocyte, during adipogenesis in cell culture, and that Pref-1 repression may be a cell fate determinant in preadipocytes.

Address correspondence to: Keith R. Yamamoto (yamamoto{at}cmp.ucsf.edu)

Abbreviations used: dex, dexamethasone; IBMX, methylisobutylxanthine; Ins, insulin; FBS, fetal bovine serum; CS, calf serum; MSC, mesenchymal stem cell; ISO, isoproterenol; C/EBP, CCAAT/enhancer-binding protein; PPAR, peroxisome proliferator-activated receptor; Pref-1, preadipocyte factor 1.

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