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Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells.
Am J Physiol Endocrinol Metab. 2006 May; 290(5):E916-24.AJ

Abstract

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/EBPbeta induction; rather, 1,25(OH)2D3 blocks the expression of C/EBPalpha, peroxisome proliferator-activated receptor-gamma (PPARgamma), 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 PPARgamma antagonist; conversely, hVDR partially suppresses the transacting activity of PPARgamma but not of C/EBPbeta or C/EBPalpha. Moreover, 1,25(OH)2D3 markedly suppresses C/EBPalpha and PPARgamma 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/EBPalpha and PPARgamma upregulation, antagonization of PPARgamma activity, and stabilization of the inhibitory VDR protein.

Authors+Show Affiliations

Kong J
Dept. of Medicine, Univ. of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA.
Li YC
No affiliation info available

MeSH

3T3-L1 CellsAdipogenesisAdipose TissueAnimalsAntineoplastic AgentsCCAAT-Enhancer-Binding Protein-alphaCCAAT-Enhancer-Binding Protein-betaCalcitriolCell DifferentiationChromansFibroblastsGene ExpressionLipoprotein LipaseMicePPAR gammaReceptors, CalcitriolRetinoid X ReceptorsSignal TransductionThiazolidinedionesTranscription Factor AP-2TransfectionTretinoinTroglitazoneVitamins

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16368784

Citation

Kong, Juan, and Yan Chun Li. "Molecular Mechanism of 1,25-dihydroxyvitamin D3 Inhibition of Adipogenesis in 3T3-L1 Cells." American Journal of Physiology. Endocrinology and Metabolism, vol. 290, no. 5, 2006, pp. E916-24.
Kong J, Li YC. Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells. Am J Physiol Endocrinol Metab. 2006;290(5):E916-24.
Kong, J., & Li, Y. C. (2006). Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells. American Journal of Physiology. Endocrinology and Metabolism, 290(5), E916-24.
Kong J, Li YC. Molecular Mechanism of 1,25-dihydroxyvitamin D3 Inhibition of Adipogenesis in 3T3-L1 Cells. Am J Physiol Endocrinol Metab. 2006;290(5):E916-24. PubMed PMID: 16368784.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells. AU - Kong,Juan, AU - Li,Yan Chun, Y1 - 2005/12/20/ PY - 2005/12/22/pubmed PY - 2006/6/20/medline PY - 2005/12/22/entrez SP - E916 EP - 24 JF - American journal of physiology. Endocrinology and metabolism JO - Am J Physiol Endocrinol Metab VL - 290 IS - 5 N2 - 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/EBPbeta induction; rather, 1,25(OH)2D3 blocks the expression of C/EBPalpha, peroxisome proliferator-activated receptor-gamma (PPARgamma), 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 PPARgamma antagonist; conversely, hVDR partially suppresses the transacting activity of PPARgamma but not of C/EBPbeta or C/EBPalpha. Moreover, 1,25(OH)2D3 markedly suppresses C/EBPalpha and PPARgamma 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/EBPalpha and PPARgamma upregulation, antagonization of PPARgamma activity, and stabilization of the inhibitory VDR protein. SN - 0193-1849 UR - https://www.unboundmedicine.com/medline/citation/16368784/Molecular_mechanism_of_125_dihydroxyvitamin_D3_inhibition_of_adipogenesis_in_3T3_L1_cells_ DB - PRIME DP - Unbound Medicine ER -