Short-chain fatty acids attenuate obesity-induced oxidative stress by regulating the MUFA/PUFA ratio in phospholipids

Obesity-induced oxidative stress contributes to metabolic disorders, and its suppression may prevent disease. While gut microbiota-derived short-chain fatty acids (SCFAs) modulate lipid metabolism, their role in oxidative stress remains unclear. Using C57BL/6 J mice and cell models (HepG2 and 3 T3-L1), this study demonstrates that SCFAs alleviate obesity-related oxidative damage in liver and adipose tissues. Mechanistically, SCFAs activate AMPKα and PPARγ, which not only inhibit lipogenesis but also interact with SCD1 to increase the monounsaturated-to-polyunsaturated fatty acid ratio (MUFA/PUFA) in phospholipids, thereby reducing lipid peroxidation in both in vivo and in vitro models. Specifically, propionate and butyrate upregulated monounsaturated phospholipids PHDdiA-Pe and PKOHA-PS. Additionally, SCFAs restore the gut microbial balance disrupted by obesity in C57BL/6 J mice. These findings provide a theoretical basis for SCFA-based dietary interventions against obesity-related diseases. • SCFAs effectively reduce oxidative stress associated with obesity. • AMPKα and PPARγ link lipid accumulation and oxidative stress. • These switches suppress lipogenesis and increase the MUFA/PUFA ratio. • Propionate and butyrate modify key phospholipids and restore gut microbiota.