Foxk1 stimulates adipogenic differentiation via a peroxisome proliferator‐activated receptor gamma 2‐dependent mechanism
Foxk1 stimulates adipogenic differentiation via a peroxisome proliferator‐activated receptor gamma 2‐dependent mechanism
复制标题
DOI：
10.1096/fj.202301153r
复制
发表时间：
2023-10
期刊：
影响因子：
--
通讯作者：
Shan Zhang;Yanru You;Yachong Li;Hairui Yuan;Jie Zhou;Lijie Tian;Ying Liu;Baoli Wang;
中科院分区：
文献类型：
--
作者：
Shan Zhang;Yanru You;Yachong Li;Hairui Yuan;Jie Zhou;Lijie Tian;Ying Liu;Baoli Wang;
脂肪生成是一个受到严格调控的过程，其功能障碍与肥胖等代谢紊乱有关。叉头盒k1 （Foxk1）已知在不同类型癌症的肌原性前体细胞分化和肿瘤发生中发挥作用；然而，目前尚不清楚它是否以及如何影响脂肪细胞分化。在这里，我们发现Foxk1在小鼠原代骨髓基质细胞（BMSCs）和建立的间充质祖/基质细胞系C3H/10T1/2和ST2中被诱导。肥胖db/db小鼠腹股沟白色脂肪组织Foxk1表达高于非肥胖db/m小鼠。Foxk1过表达可促进C3H/10T1/2、ST2细胞和骨髓间充质干细胞的成脂分化，同时CCAAT/增强子结合蛋白α、过氧化物酶体增殖物激活受体γ (Pparγ)和脂肪酸结合蛋白4的表达增强。此外，Foxk1过表达增强了C3H/10T1/2细胞和骨髓间充质干细胞成脂分化过程中脂质因子的表达水平。相反，Foxk1沉默会损害这些细胞的完全分化。此外，脂肪生成刺激诱导Foxk1的核易位，这依赖于mTOR和PI3激酶信号通路。随后，Foxk1直接与ppar γ - 2启动子结合，刺激其转录活性，促进脂肪细胞分化。总之，我们的研究提供了Foxk1在脂肪形成分化过程中通过促进核易位和上调ppar γ - 2启动子的转录活性来促进祖细胞向脂肪细胞分化的第一个证据。
Adipogenesis is a tightly regulated process, and its dysfunction has been linked to metabolic disorders such as obesity. Forkhead box k1 (Foxk1) is known to play a role in the differentiation of myogenic precursor cells and tumorigenesis of different types of cancers; however, it is not clear whether and how it influences adipocyte differentiation. Here, we found that Foxk1 was induced in mouse primary bone marrow stromal cells (BMSCs) and established mesenchymal progenitor/stromal cell lines C3H/10T1/2 and ST2 after adipogenic treatment. In addition, obese db/db mice have higher Foxk1 expression in inguinal white adipose tissue than nonobese db/m mice. Foxk1 overexpression promoted adipogenic differentiation of C3H/10T1/2, ST2 cells and BMSCs, along with the enhanced expression of CCAAT/enhancer binding protein‐α, peroxisome proliferator‐activated receptor γ (Pparγ), and fatty acid binding protein 4. Moreover, Foxk1 overexpression enhanced the expression levels of lipogenic factors during adipogenic differentiation in both C3H/10T1/2 cells and BMSCs. Conversely, Foxk1 silencing impaired these cells from fully differentiating. Furthermore, adipogenic stimulation induced the nuclear translocation of Foxk1, which depended on the mTOR and PI3‐kinase signaling pathways. Subsequently, Foxk1 is directly bound to the Pparγ2 promoter, stimulating its transcriptional activity and promoting adipocyte differentiation. Collectively, our study provides the first evidence that Foxk1 promotes adipocyte differentiation from progenitor cells by promoting nuclear translocation and upregulating the transcriptional activity of the Pparγ2 promoter during adipogenic differentiation.