Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research, University of Innsbruck, Rennweg 10, 6020 Innsbruck, Austria.
J Gerontol A Biol Sci Med Sci. 2013 Nov;68(11):1356-76. doi: 10.1093/gerona/glt019. Epub 2013 Mar 22.
We show that resveratrol prevents clonal expansion and terminal adipogenesis in 3T3-L1 preadipocytes. An early resveratrol effect was the inhibition of AKT and mitogen-activated protein kinase signaling, accompanied by down regulation of cyclin D1 expression, abrogation of retinoblastoma protein hyperphosphorylation, and subsequent inhibition of cell cycle reentry and clonal expansion, as indicated by cyclin A2 repression. Resveratrol inhibited terminal adipogenesis at the level of peroxisome proliferator-activated receptor-γ2 expression and activity. This was independent from the preceding inhibition of clonal expansion. Peroxisome proliferator-activated receptor-γ2 overexpression and activation partially restored fatty acid-binding protein 4 induction in resveratrol-treated 3T3-L1. Resveratrol activated AMP-activated protein kinase (AMPK) but did not induce PPAR-γ co-activator 1α (PGC1α) and mitochondrial biogenesis in 3T3-L1. Treatment with the Sirt1 inhibitor splitomicin augmented downregulation of peroxisome proliferator-activated receptor-γ2 and fatty acid-binding protein 4 expressions in resveratrol-treated 3T3-L1 and did not prevent the inhibition of terminal adipogenesis. Moreover, splitomicin could not obviate resveratrol-induced cyclin D1 repression, retinoblastoma protein hypophosphorylation, and inhibition of clonal expansion. Our data suggest that resveratrol inhibits clonal expansion and terminal adipogenesis in 3T3-L1 by several mechanisms.
我们表明白藜芦醇可防止 3T3-L1 前脂肪细胞的克隆扩张和终末脂肪生成。白藜芦醇的早期作用是抑制 AKT 和有丝分裂原激活的蛋白激酶信号通路，同时下调细胞周期蛋白 D1 的表达，取消视网膜母细胞瘤蛋白的过度磷酸化，随后抑制细胞周期再进入和克隆扩张，这表现为细胞周期蛋白 A2 的抑制。白藜芦醇通过过氧化物酶体增殖物激活受体-γ2 的表达和活性来抑制终末脂肪生成。这与之前抑制克隆扩张是独立的。过氧化物酶体增殖物激活受体-γ2 的过表达和激活部分恢复了脂肪酸结合蛋白 4 在白藜芦醇处理的 3T3-L1 中的诱导。白藜芦醇激活 AMP 激活的蛋白激酶（AMPK），但不会诱导过氧化物酶体增殖物激活受体-γ2 的共激活物 1α（PGC1α）和线粒体生物发生在 3T3-L1 中。用 Sirt1 抑制剂 splitomicin 处理会增强白藜芦醇处理的 3T3-L1 中过氧化物酶体增殖物激活受体-γ2 和脂肪酸结合蛋白 4 的下调，但不能防止终末脂肪生成的抑制。此外，splitomicin 不能消除白藜芦醇诱导的细胞周期蛋白 D1 下调、视网膜母细胞瘤蛋白低磷酸化和克隆扩张的抑制。我们的数据表明，白藜芦醇通过多种机制抑制 3T3-L1 中的克隆扩张和终末脂肪生成。
