Obesity is the main risk factor behind insulin resistance and type 2 diabetes. Still, the mechanism behind adipocyte dysfunction is not yet resolved. Recently, we reported that rapid actin remodeling correlates with adipose cell size changes after short-term overfeeding. Therefore, we hypothesized that the actin-driven myocardin-related transcription factor (MRTF-A) contributes to impaired mature adipocyte function.

Primary human adipocytes were subjected to adenoviral overexpression of MRTF-A or MRTF-B, followed by Western blot analysis and tracer glucose uptake assay. Further, we assessed cell size distribution, insulin response, MRTF-A localization, actin organization and degree of polymerization in adipocytes isolated from Ob/Ob mice.

Overexpression of MRTF-A, but not MRTF-B, markedly suppressed PPARγ expression. Further, MRTF-A expression resulted in decreased IRS-1 level, shifted phosphorylation of Akt (pS473/pT308), IRS-1 (pS302) and AS160 (pT642), and lowered insulin-stimulated glucose uptake. Hypertrophic adipocytes from Ob/Ob mice displayed an increased proportion of polymerized actin, and increased nuclear translocation of MRTF-A compared with control (Ob/+). Similar with human adipocytes overexpressing MRTF-A, adipocytes isolated from Ob/Ob mice had reduced expression of IRS-1 and PPARγ, as well as impaired insulin response.

Together, these data demonstrate that MRTF-A negatively influences insulin sensitivity and the expression of key targets in fully mature human adipocytes. This suggests that MRTF-A is poised to exert a transcriptional response in hypertrophic adipocytes, contributing to adipocyte dysfunction and insulin resistance.

肥胖是胰岛素抵抗和2型糖尿病背后的主要危险因素。脂肪细胞功能障碍的机制仍未解决。最近，我们报道了肌动蛋白的快速重塑与短期过量摄食后脂肪细胞大小的变化有关。因此，我们假设肌动蛋白驱动的心肌相关转录因子（MRTF-A）有助于成熟的脂肪细胞功能受损。

将原代人脂肪细胞进行MRTF-A或MRTF-B的腺病毒过表达，然后进行蛋白质印迹分析和示踪葡萄糖摄取测定。此外，我们评估了分离自Ob / Ob小鼠的脂肪细胞的细胞大小分布，胰岛素应答，MRTF-A定位，肌动蛋白组织和聚合度。

MRTF-A（而非MRTF-B）的过表达显着抑制了PPARγ的表达。此外，MRTF-A的表达导致IRS-1水平降低，Akt（pS473 / pT308），IRS-1（pS302）和AS160（pT642）磷酸化，并降低了胰岛素刺激的葡萄糖摄取。与对照（Ob / +）相比，来自Ob / Ob小鼠的肥大性脂肪细胞显示出增加的聚合肌动蛋白比例，并增加了MRTF-A的核转运。与过量表达MRTF-A的人脂肪细胞相似，从Ob / Ob小鼠分离的脂肪细胞IRS-1和PPARγ的表达降低，并且胰岛素反应受损。

总之，这些数据表明，MRTF-A对胰岛素敏感性和完全成熟的人类脂肪细胞中关键靶标的表达产生负面影响。这表明MRTF-A有望在肥厚性脂肪细胞中发挥转录反应，从而导致脂肪细胞功能障碍和胰岛素抵抗。