Mechanistic study of FA-PG3 nanoparticles promoting adipose browning through the PPARγ and PRDM16-UCP1 pathway in severe pediatric obesity

Food-derived bioactive compounds offer an attractive and sustainable approach to metabolic disease prevention, yet mechanistic evidence supporting their efficacy in pediatric obesity remains limited. This study investigates the thermogenic potential of ferulic acid (FA), a plant-derived phenolic compound, when delivered via a dendrimer-based nanocarrier. Using an integrative strategy combining network pharmacology, molecular docking, cellular assays, animal models, and clinical biomarker analysis, we demonstrate that FA-loaded generation 3 PAMAM nanoparticles (FA-PG3) effectively activate adipose tissue thermogenesis. Computational analyses identified UCP1 as a central molecular target of FA, with PPARγ and PRDM16 acting as critical upstream regulators. FA-PG3 nanoparticles exhibited optimized nanoscale properties and sustained FA release. In vitro, FA-PG3 promoted beige adipocyte differentiation, enhanced mitochondrial respiration, and increased thermogenic gene expression. In vivo, FA-PG3 improved energy expenditure, insulin sensitivity, and adipose browning in obese mice, while UCP1 silencing largely abolished these metabolic benefits. Notably, children with severe obesity exhibited significantly lower circulating levels of browning-associated adipokines, supporting the clinical relevance of targeting thermogenic pathways. Our findings highlight a previously underappreciated food-derived, nano-enabled strategy for metabolic reprogramming and position FA-PG3 as a promising translational candidate for addressing pediatric obesity through adipose tissue thermogenesis.