Diabetes and Beta Cell Biology Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Department of Diabetes Complications & Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
Mol Cell Endocrinol. 2020 Sep 15;515:110920. doi: 10.1016/j.mce.2020.110920. Epub 2020 Jun 27.
The SRF/MRTF and upstream signaling cascade play key roles in actin cytoskeleton organization and myocyte development. To date, how this signaling axis may function in brown adipocyte lineage commitment and maturation has not been delineated. Here we report that MRTF-SRF signaling exerts inhibitory actions on brown adipogenesis, and suppressing this negative regulation promotes brown adipocyte lineage development. During brown adipogenic differentiation, protein expressions of SRF, MRTFA/B and its transcription targets were down-regulated, and MRTFA/B shuttled from nucleus to cytoplasm. Silencing of SRF or MRTF-A/MRTF-B enhanced two distinct stages of brown adipocyte development, mesenchymal stem cell determination to brown adipocytes and terminal differentiation of brown adipogenic progenitors. We further demonstrate that the MRTF-SRF axis exerts transcriptional regulations of the TGF-β and BMP signaling pathway, critical developmental cues for brown adipocyte development. TGF-β signaling activity was significantly attenuated, whereas that of the BMP pathway augmented by inhibition of SRF or MRTF-A/MRTF-B, leading to enhanced brown adipocyte differentiation. Our study demonstrates the MRTF-SRF transcriptional cascade as a negative regulator of brown adipogenesis, through its transcriptional control of the TGF-β/BMP signaling pathways.
SRF/MRTF 和上游信号级联在肌动蛋白细胞骨架组织和心肌细胞发育中发挥关键作用。迄今为止，该信号轴如何在棕色脂肪细胞谱系的决定和成熟中发挥作用尚不清楚。在这里，我们报告 MRTF-SRF 信号对棕色脂肪生成具有抑制作用，抑制这种负调控可促进棕色脂肪细胞谱系的发育。在棕色脂肪生成分化过程中，SRF、MRTFA/B 和其转录靶标的蛋白表达水平下调，MRTFA/B 从细胞核转位到细胞质。沉默 SRF 或 MRTF-A/B 增强了棕色脂肪细胞发育的两个不同阶段，即间充质干细胞向棕色脂肪细胞的决定和棕色脂肪生成前体细胞的终末分化。我们进一步证明，MRTF-SRF 轴对 TGF-β 和 BMP 信号通路具有转录调控作用，该通路对棕色脂肪细胞的发育至关重要。通过抑制 SRF 或 MRTF-A/B，TGF-β 信号活性显著减弱，而 BMP 通路活性增强，导致棕色脂肪细胞分化增强。我们的研究表明，MRTF-SRF 转录级联通过其对 TGF-β/BMP 信号通路的转录调控，作为棕色脂肪生成的负调控因子。
