Nrf2/HO-1 Activation Mediates the Anti-Adipogenic and Browning Effects of Phloroglucinol in 3T3-L1 Adipocytes

Phloroglucinol (PG) is a naturally occurring phenolic compound and the fundamental monomeric unit of marine phlorotannins, yet its effects on adipocyte differentiation and browning remain incompletely understood. This study investigated whether PG inhibits adipogenesis and induces browning markers in 3T3-L1 adipocytes through Nrf2/HO-1 pathway activation. Differentiating 3T3-L1 cells were treated with PG (10, 50, and 100 µM) with or without ZnPP (5 µM), a specific HO-1 inhibitor. PG concentration-dependently reduced lipid accumulation and intracellular cholesterol and triglyceride levels, while suppressing PPARγ, C/EBPα, FAS, and aP2 protein expression. PG also upregulated the browning markers UCP1, PGC-1α, and PRDM16, and activated AMPK. Mechanistically, PG promoted Nrf2 nuclear translocation and increased HO-1 expression, accompanied by reduced ROS production and enhanced SOD, GPx, and CAT activities. Notably, ZnPP co-treatment reversed all these effects—lipid accumulation returned toward control levels, adipogenic markers increased, browning markers decreased, and antioxidant enzyme activities were attenuated—while Nrf2 nuclear translocation and HO-1 protein expression remained elevated. These findings demonstrate that PG inhibits adipogenesis and induces browning markers through an HO-1-dependent mechanism, with ZnPP experiments confirming that HO-1 activity is functionally required for these effects. This is the first study to establish a causal link between Nrf2/HO-1 activation and the anti-adipogenic effects and browning marker upregulation of PG in adipocytes. Given PG’s established safety profile as an approved antispasmodic agent, these findings support its potential as a multi-target therapeutic candidate for obesity and related metabolic disorders.