Flavonoid-based dual modulation of GPR120 and PPARγ: A potential therapeutic strategy for metabolic disease intervention.

Type 2 diabetes mellitus (T2DM) remains a major metabolic disorder requiring the development of novel therapeutics. GPR120, a G-protein-coupled receptor involved in metabolic regulation, has emerged as a promising target; however, potent agonists are still scarce, underscoring the need for new candidates. In this study, we designed and synthesized a series of flavone and isoflavone derivatives to identify potent GPR120 agonists. Among 16 derivatives, 4',5,7-trimethoxyflavone (15) exhibited the highest potency with an EC₅₀ of 0.6 μM. Biological assays revealed that 15 significantly enhanced glucose uptake in 3T3-L1 adipocytes through GPR120-mediated AMPK phosphorylation and reduced adipogenesis by modulating early differentiation markers. Furthermore, in a zebrafish larva model, 15 influenced the expression of pre-insulin markers, indicating systemic metabolic effects. Notably, 15 also demonstrated potent PPARγ antagonist activity, highlighting its dual role in modulating key metabolic pathways. These findings support 15 as a promising lead for developing safer, dual-acting therapeutics for T2DM and metabolic syndrome.