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Molecular mechanism of 1,25-dihydroxyvitamin D₃ inhibition of adipogenesis in 3T3-L1 cells

¹Department of Medicine and ²Committee on Molecular Metabolism and Nutrition, The University of Chicago, Chicago, Illinois

Submitted 30 August 2005 ; accepted in final form 16 December 2005

We have investigated the molecular mechanism whereby 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] inhibits adipogenesis in vitro. 1,25(OH)₂D₃ blocks 3T3-L1 cell differentiation into adipocytes in a dose-dependent manner; however, the inhibition is ineffective 24–48 h after the differentiation is initiated, suggesting that 1,25(OH)₂D₃ inhibits only the early events of the adipogenic program. Treatment of 3T3-L1 cells with 1,25(OH)₂D₃ does not block the mitotic clonal expansion or C/EBP induction; rather, 1,25(OH)₂D₃ blocks the expression of C/EBP, peroxisome proliferator-activated receptor- (PPAR), sterol regulatory element-binding protein-1, and other downstream adipocyte markers. The inhibition by 1,25(OH)₂D₃ is reversible, since removal of 1,25(OH)₂D₃ from the medium restores the adipogenic process with only a temporal delay. Interestingly, although the vitamin D receptor (VDR) protein is barely detectable in 3T3-L1 preadipocytes, its levels are dramatically increased during the early phase of adipogenesis, peaking at 4–8 h and subsiding afterward throughout the rest of the differentiation program; 1,25(OH)₂D₃ treatment appears to stabilize the VDR protein levels. Consistently, adenovirus-mediated overexpression of human (h) VDR in 3T3-L1 cells completely blocks the adipogenic program, confirming that VDR is inhibitory. Inhibition of adipocyte differentiation by 1,25(OH)₂D₃ is ameliorated by troglitazone, a specific PPAR antagonist; conversely, hVDR partially suppresses the transacting activity of PPAR but not of C/EBP or C/EBP. Moreover, 1,25(OH)₂D₃ markedly suppresses C/EBP and PPAR mRNA levels in mouse epididymal fat tissue culture. Taken together, these data indicate that the blockade of 3T3-L1 cell differentiation by 1,25(OH)₂D₃ occurs at the postclonal expansion stages and involves direct suppression of C/EBP and PPAR upregulation, antagonization of PPAR activity, and stabilization of the inhibitory VDR protein.

vitamin D; vitamin D receptor; adipocyte differentiation

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