N. Perumal, Amila Mufida, A. Yadav
Feb 1, 2023
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Life
Abstract
Simple Summary p38 MAPK is emerging as a novel regulator in (pre)adipocyte differentiation. TAK-715 is a selective inhibitor of p38 MAPK, but its anti-adipogenic effect and mechanism during the differentiation of preadipocytes and human adipose stem cells (hASCs) into adipocytes remain unclear. In this study, a treatment with TAK-715 (10 μM) led to a marked inhibition of lipid accumulation during the adipocyte differentiation of 3T3-L1 preadipocytes and hASCs. TAK-715 further downregulated the expression and phosphorylation of C/EBP-α, PPAR-γ, STAT-3, FAS, perilipin A, p38 MAPK, and its downstream effector ATF-2 during 3T3-L1 cells and hASCs differentiation. Taken together, this is the first report that shows TAK-715 has a strong lipid-lowering effect during the adipocyte differentiation of 3T3-L1 preadipocytes and hASCs by regulating the expression and phosphorylation of C/EBP-α, PPAR-γ, STAT-3, FAS, perilipin A, ATF-2, and p38 MAPK. In this work, TAK-715 is proposed as a potential preventive or therapeutic agent for managing obesity. Abstract 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.