期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 290, 期 5, 页码 E916-E924出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00410.2005
关键词
vitamin D; vitamin D receptor; adipocyte differentiation
资金
- NIDDK NIH HHS [DK-59327] Funding Source: Medline
We have investigated the molecular mechanism whereby 1,25-dihydroxyvitamin D-3 [ 1,25( OH)(2)D-3] inhibits adipogenesis in vitro. 1,25( OH)(2)D-33 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)(2)D-3 inhibits only the early events of the adipogenic program. Treatment of 3T3-L1 cells with 1,25( OH)(2)D-3 does not block the mitotic clonal expansion or C/EBP beta induction; rather, 1,25( OH)(2)D-3 blocks the expression of C/EBP beta, peroxisome proliferator-activated receptor-gamma ( PPAR gamma), sterol regulatory element-binding protein-1, and other downstream adipocyte markers. The inhibition by 1,25( OH)(2)D-3 is reversible, since removal of 1,25( OH)(2)D-3 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)(2)D-3 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)(2)D-3 is ameliorated by troglitazone, a specific PPAR gamma antagonist; conversely, hVDR partially suppresses the transacting activity of PPAR gamma but not of C/EBP beta or C/EBP alpha. Moreover, 1,25( OH)(2)D-3 markedly suppresses C/EBP alpha and PPAR gamma 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)(2)D-3 occurs at the postclonal expansion stages and involves direct suppression of C/EBP alpha and PPAR alpha upregulation, antagonization of PPAR gamma activity, and stabilization of the inhibitory VDR protein.
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