Xue J C, Schwarz E J, Chawla A, Lazar M A
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.
Mol Cell Biol. 1996 Apr;16(4):1567-75. doi: 10.1128/MCB.16.4.1567.
Retinoic acid (RA) inhibits adipocyte differentiation of 3T3-L1 preadipocytes but is effective only early in adipogenesis. RA prevented induction of the adipogenic factors PPARgamma and C/EBPalpha. Using receptor-specific ligands, we determined that the effects of RA were mediated by liganded RA receptors (RARs) rather than retinoid X receptors. Preadipocytes expressed primarily RARalpha and RARgamma; during adipocyte differentiation, RARalpha gene expression was nearly constant, whereas RARgamma1 mRNA and protein levels dramatically decreased. Ectopic expression of RARgamma1 extended the period of effectiveness of RA by 24 to 48h; RARalpha expression had a similar effect, suggesting functional redundancy of RAR subtypes. Remarkably, RA inhibited differentiation when added after PPARgamma1 and PPARgamma2 proteins had already been expressed and resulted in the loss of PPARgamma proteins from cells. By 72 to 96 h after the induction of differentiation, RA failed to prevent differentiation of even ectopic-RAR-expressing cells. Thus, the unresponsiveness of 3T3-L1 preadipocytes to RA after the induction of differentiation is initially due to the reduction in cellular RAR concentration rather than to the induction of PPARgamma. At later times cells continue along the differentiation pathway in a manner which is RA and RAR independent.
视黄酸（RA）可抑制3T3-L1前脂肪细胞的脂肪生成，但仅在脂肪生成早期有效。RA可阻止脂肪生成因子PPARγ和C/EBPα的诱导。使用受体特异性配体，我们确定RA的作用是由配体化的视黄酸受体（RARs）介导的，而非视黄醇X受体。前脂肪细胞主要表达RARα和RARγ；在脂肪细胞分化过程中，RARα基因表达几乎恒定，而RARγ1 mRNA和蛋白水平显著下降。RARγ1的异位表达使RA的有效作用时间延长了24至48小时；RARα表达也有类似作用，提示RAR亚型存在功能冗余。值得注意的是，当PPARγ1和PPARγ2蛋白已经表达后添加RA，仍可抑制分化，并导致细胞中PPARγ蛋白丢失。在诱导分化后72至96小时，即使是异位表达RAR的细胞，RA也无法阻止其分化。因此，3T3-L1前脂肪细胞在诱导分化后对RA无反应，最初是由于细胞RAR浓度降低，而非PPARγ的诱导。在后期，细胞以一种与RA和RAR无关的方式继续沿着分化途径发展。
