Quercetin and silibinin ameliorate insulin resistance by stimulating fat browning via the β3-AR/AMPK pathway in palmitate-exposed 3T3-F442A adipocytes

Quercetin (QC) and silibinin (SLB), natural bioactive compounds from medicinal plants, show potential in improving IR. However, the molecular mechanisms underlying their IR-attenuating effects through adipocyte browning remain not fully elucidated. In this study, molecular docking simulations were performed to characterize ligand-target interactions, binding conformations, and affinity energies between QC/SLB and key molecular targets. qRT-PCR and immunoblotting analyses were employed to quantify expression levels of β3-AR/AMPK pathway-associated genes and proteins. Notably, QC and SLB upregulated brown/beige adipocyte markers at transcriptional and translational levels: PGC-1α, PRDM16, and UCP1, and genes specific to beige adipose tissue like Tmem26, Tbx1, CD137, and Cited1. Mechanistically, these compounds enhanced lipolytic activity and β-oxidation throughβ3-AR-mediated activation of PKA, ATGL, CPT, ACO, and PPARα/γ signaling cascades. Overall, QC and SLB promote PA-induced adipocyte browning in IR-3T3-F442A cells by activating both the β3-AR/AMPK signaling pathways, highlighting their potential as therapeutic agents for metabolic disorders. Our findings collectively demonstrate the potential effectiveness of QC and SLB in ameliorating IR.