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Modulator Recognition Factor-2 Is Required for Adipogenesis in Mouse Embryo Fibroblasts and 3T3-L1 Cells

Department of Molecular Biology, City of Hope Beckman Research Institute, Duarte, California 91010

Address all correspondence and requests for reprints to: Keiichi Itakura, Department of Molecular Biology, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, California 91010. E-mail: KItakura{at}coh.org.

Previous study showed that mice lacking modulator recognition factor-2 (Mrf-2) were lean, with significant decreases in white adipose tissue. One postulated mechanism for the lean phenotype in Mrf-2 knockout mice is a defect in adipogenesis. In order to investigate this further, we examined the effects of Mrf-2 deficiency on adipogenesis in vitro. In mouse fibroblasts (MEFs) derived from Mrf-2^–/– embryos, and in 3T3-L1 cells after knockdown of Mrf-2 by small interference RNA (siRNA) there was a potent inhibition of hormone-induced lipid accumulation, and significant decreases in the expression of the adipogenic transcription factors CCAAT/enhancer-binding protein (C/EBP) and peroxisome proliferator-activated receptor- and the mature adipocyte genes they control. Transduction of Mrf-2^–/– MEFs with a retroviral vector expressing the longer Mrf-2 splice variant (Mrf-2B) stimulated both gene expression and lipid accumulation. Because 3T3-L1 cells are committed to the adipocyte lineage, we used this simpler model system to examine the effects of Mrf-2 deficiency on adipocyte maturation. Analyses of both mRNA and protein revealed that knockdown of Mrf-2 in 3T3-L1 cells prolonged the expression of C/EBP homologous protein-10, a dominant-negative form of C/EBP. Consistent with these findings, suppression of Mrf-2 also inhibited the DNA-binding activity of C/EBPβ. These data suggest that Mrf-2 facilitates the induction of the two key adipogenic transcription factors C/EBP and peroxisome proliferator-activated receptor- indirectly by permitting hormone-mediated repression of the adipogenic repressor C/EBP homologous protein-10.

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Nuclear Receptors:   PPARγ