过度的前脂肪细胞分化与肥胖有关。尽管以前的研究表明p38MAPK与脂肪形成有关,p38丝裂原活化蛋白激酶(MAPK)抑制剂TAK-715对前脂肪细胞分化的调节,尚不清楚。有趣的是,10μM的TAK-715在3T3-L1前脂肪细胞分化过程中极大地抑制了脂质和细胞内甘油三酯(TG)含量的积累,而没有细胞毒性。在机械层面上,TAK-715显著降低CCAAT/增强子结合蛋白-α(C/EBP-α)的表达,过氧化物酶体增殖物激活受体γ(PPAR-γ),脂肪酸合成酶(FAS),和perilipinA同样,通过TAK-715处理,分化中的3T3-L1细胞中的信号转导子和转录激活子-3(STAT-3)的磷酸化也降低.此外,TAK-715显著阻断激活转录因子-2(ATF-2)的磷酸化,p38MAPK下游分子,在3T3-L1前脂肪细胞分化过程中。重要的是,在人脂肪干细胞(hASC)的脂肪细胞分化过程中,TAK-715还显著阻碍p38MAPK的磷酸化并抑制脂质积累。简洁地说,这是首次报道TAK-715(10μM)通过调节p38MAPK的表达和磷酸化对3T3-L1细胞和hASCs的脂肪形成过程具有有效的抗脂肪生成作用,C/EBP-α,PPAR-γ,STAT-3,FAS,
Excessive preadipocyte differentiation is linked with obesity. Although previous studies have shown that p38 MAPK is associated with adipogenesis, the regulation of preadipocyte differentiation by TAK-715, an inhibitor of p38 mitogen-activated protein kinase (MAPK), remains unclear. Interestingly, TAK-715 at 10 μM vastly suppressed the accumulation of lipid and intracellular triglyceride (TG) content with no cytotoxicity during 3T3-L1 preadipocyte differentiation. On mechanistic levels, TAK-715 significantly decreased the expressions of the CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor gamma (PPAR-γ), fatty acid synthase (FAS), and perilipin A. Similarly, the phosphorylation of the signal transducer and activator of transcription-3 (STAT-3) in differentiating 3T3-L1 cells was also reduced with TAK-715 treatment. Moreover, TAK-715 significantly blocked the phosphorylation of activating transcription factor-2 (ATF-2), a p38 MAPK downstream molecule, during 3T3-L1 preadipocyte differentiation. Of importance, TAK-715 also markedly impeded the phosphorylation of p38 MAPK and suppressed lipid accumulation during the adipocyte differentiation of human adipose stem cells (
hASCs). Concisely, this is the first report that TAK-715 (10 μM) has potent anti-adipogenic effects on the adipogenesis process of 3T3-L1 cells and
hASCs through the regulation of the expression and phosphorylation of p38 MAPK, C/EBP-α, PPAR-γ, STAT-3, FAS, and perilipin A.