Free Fatty Acids and LPS Synergistically Promote Macrophage M1 Polarization and Insulin Resistance Via FTO-Mediated CSF1 Degradation

Free fatty acids (FFA) and lipopolysaccharide (LPS) synergistically exacerbate metabolic inflammation, but the underlying mechanisms remain unclear. This study investigates how FFA and LPS cooperatively promote macrophage M1 polarization and insulin resistance (IR). In vivo models (HFD-fed and LPS-treated mice) and in vitro macrophage assays were employed. Flow cytometry, RNA-seq, m6A methylation analysis, and AAV-mediated gene modulation of FTO or CSF1 were used to dissect mechanisms. Metabolic phenotypes in mice were assessed via fasting blood glucose and HOMA-IR index. Combined FFA and LPS treatment synergistically increased M1 macrophage polarization and IR, correlating with elevated FTO expression. FTO upregulated by FFA/LPS reduced m6A modification of CSF1 mRNA, promoting its degradation via impaired IGF2BP2 binding. Depleting FTO or restoring CSF1 attenuated M1 polarization and improved insulin sensitivity in vivo. The FTO-m6A-CSF1 axis drives FFA/LPS-induced metabolic inflammation, offering therapeutic targets for IR.