Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary.
Institute of Physiology, Medical School University of Pécs, 7622 Pécs, Hungary.
Cells. 2019 Aug 5;8(8):831. doi: 10.3390/cells8080831.
Obesity and adipocyte malfunction are related to and arise as consequences of disturbances in signaling pathways. Tyrosine kinase substrate with four Src homology 3 domains (Tks4) is a scaffold protein that establishes a platform for signaling cascade molecules during podosome formation and epidermal growth factor receptor (EGFR) signaling. Several lines of evidence have also suggested that Tks4 has a role in adipocyte biology; however, its roles in the various types of adipocytes at the cellular level and in transcriptional regulation have not been studied. Therefore, we hypothesized that Tks4 functions as an organizing molecule in signaling networks that regulate adipocyte homeostasis. Our aims were to study the white and brown adipose depots of Tks4 knockout (KO) mice using immunohistology and western blotting and to analyze gene expression changes regulated by the white, brown, and beige adipocyte-related transcription factors via a PCR array. Based on morphological differences in the Tks4-KO adipocytes and increased uncoupling protein 1 (UCP1) expression in the white adipose tissue (WAT) of Tks4-KO mice, we concluded that the beigeing process was more robust in the WAT of Tks4-KO mice compared to the wild-type animals. Furthermore, in the Tks4-KO WAT, the expression profile of peroxisome proliferator-activated receptor gamma (PPARγ)-regulated adipogenesis-related genes was shifted in favor of the appearance of beige-like cells. These results suggest that Tks4 and its downstream signaling partners are novel regulators of adipocyte functions and PPARγ-directed white to beige adipose tissue conversion.
肥胖和脂肪细胞功能障碍与信号通路紊乱有关，并由此产生。具有四个Src 同源 3 结构域的酪氨酸激酶底物 (Tks4) 是一种支架蛋白，它在足突形成和表皮生长因子受体 (EGFR) 信号传导过程中为信号级联分子建立平台。有几条证据表明 Tks4 在脂肪细胞生物学中具有作用；然而，其在各种类型的脂肪细胞中的作用以及在转录调节中的作用尚未得到研究。因此，我们假设 Tks4 作为调节脂肪细胞稳态的信号网络中的组织分子发挥作用。我们的目的是使用免疫组织化学和蛋白质印迹技术研究 Tks4 敲除 (KO) 小鼠的白色和棕色脂肪组织，并通过 PCR 阵列分析受白色、棕色和米色脂肪细胞相关转录因子调节的基因表达变化。基于 Tks4-KO 脂肪细胞的形态差异和 Tks4-KO 小鼠白色脂肪组织 (WAT) 中解偶联蛋白 1 (UCP1) 表达增加，我们得出结论，与野生型动物相比，Tks4-KO 小鼠的 WAT 中米色化过程更为强烈。此外，在 Tks4-KO WAT 中，过氧化物酶体增殖物激活受体 γ (PPARγ) 调节的脂肪生成相关基因的表达谱向出现米色样细胞的方向转变。这些结果表明，Tks4 及其下游信号伙伴是脂肪细胞功能和 PPARγ 指导的白色至米色脂肪组织转化的新型调节剂。
