PAK4 phosphorylates cyclin-dependent kinase 2 to promote the G1/S transition during adipogenesis

p21-activated kinase 4 (PAK4), a member of the PAK family (PAK1-6), was initially recognized for its role in tumor development. Recently, we discovered PAK4's involvement in triacylglycerol lipolysis in adipocytes. However, its function in adipogenesis remains unclear. Here we show that PAK4 plays a critical role in adipocyte differentiation. Following adipogenic stimulation, PAK4 protein levels increased. Knockdown of PAK4 in 3T3-L1 preadipocytes or human stromal vascular cells, as well as pharmacological inhibition of PAK4 in 3T3-L1 cells, impaired adipogenesis, as indicated by reduced expression of adipocyte marker genes and decreased lipid accumulation. Mechanistically, PAK4 phosphorylated cyclin-dependent kinase 2 at serine 106, a critical step for CCAAT/enhancer-binding protein β expression during mitotic clonal expansion. Consistent with these findings, preadipocyte-specific Pak4-knockout mice exhibited reduced fat mass and smaller adipocytes. These results reveal PAK4 as a crucial regulator of adipogenesis and, together with its inhibitory role in triacylglycerol lipolysis, further underscore its potential as a therapeutic target for obesity treatment.