BIX02189 Suppresses Adipogenesis and Lipid Accumulation Through Inhibition of MEK5-STAT3/STAT5 Signaling and Activation of AMPK in Adipocytes and Zebrafish.

Obesity is a major metabolic disorder characterized by excessive lipid accumulation and adipocyte differentiation. The mitogen-activated protein kinase kinase 5 (MEK5) signaling pathway has been implicated in diverse cellular processes; however, its role in adipogenesis remains incompletely understood. In this study, we investigated the anti-adipogenic effects of BIX02189, a selective MEK5 inhibitor, using 3T3-L1 adipocytes, human adipose-derived stem cells (hASCs), and zebrafish models. Treatment with BIX02189 significantly reduced lipid accumulation and triglyceride content during adipocyte differentiation in a dose-dependent manner without marked cytotoxicity. BIX02189 effectively suppressed MEK5 phosphorylation and downregulated the expression of key adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma (PPAR-γ) and CCAAT/enhancer-binding protein alpha (C/EBP-α). In addition, BIX02189 decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and STAT5, as well as the expression of lipogenic markers such as fatty acid synthase (FAS), perilipin A, and leptin. Conversely, BIX02189 enhanced AMP-activated protein kinase (AMPK) phosphorylation and markedly reduced the protein and mRNA expression of acetyl-CoA carboxylase (ACC), a key enzyme involved in fatty acid synthesis. Similar anti-adipogenic effects were observed in hASCs. Furthermore, BIX02189 significantly attenuated lipid accumulation in a zebrafish obesity model without affecting body length or causing overt toxicity. Collectively, these findings demonstrate that pharmacological inhibition of MEK5 suppresses adipogenesis and lipid accumulation through regulation of the STAT3/STAT5-PPAR-γ axis and activation of AMPK signaling. These findings provide the first evidence that MEK5 inhibition exerts anti-adipogenic effects in adipocytes and zebrafish, highlighting the MEK5 signaling pathway as a previously unrecognized regulator of adipogenesis and lipid metabolism.