Obesity-related type 2 diabetes mellitus (O&T2DM) has become a major global public health issue. Chronic low-grade inflammation in adipose tissue is one of its core pathological features, among which excessive infiltration of M1-type macrophages and impaired function of M2-type macrophages are key drivers of inflammation. Liraglutide, a glucagon-like peptide-1 receptor agonist, exhibits significant glucose-lowering, weight-reducing, and anti-inflammatory effects. However, the molecular mechanisms by which liraglutide regulates cholesterol metabolism and epigenetic modifications in adipose tissue macrophages remain to be fully elucidated. A high-fat diet combined with streptozotocin was used to establish an O&T2DM model in male C57BL/6 mice. After 8 weeks of intervention, metabolic phenotypes, adipose tissue macrophage polarization, and cholesterol metabolism-related indicators were assessed. Raw264.7 macrophages were cultured in vitro and stimulated with IFN-γ + LPS to induce M1 polarization. Following liraglutide pretreatment, cell polarization phenotypes, the expression of genes involved in cholesterol metabolic pathways, and histone modification levels were examined. Using shRNA gene silencing, p300 inhibitor intervention, and Acetyl-CoA supplementation experiments in combination with ChIP-qPCR, the central role of the cholesterol metabolism-epigenetic axis in macrophage polarization was elucidated. Finally, a Transwell co-culture system was employed to verify the regulatory effects of liraglutide-reprogrammed macrophages on adipocyte lipid accumulation and energy metabolism. Liraglutide significantly reduced body weight, fasting blood glucose, and HOMA-IR in O&T2DM mice, decreased visceral fat accumulation, and promoted adipose tissue browning. It also increased the proportion of M2 macrophages within adipose tissue and significantly activated the key cholesterol efflux pathway LXRα/ABCA1. In vitro experiments confirmed that liraglutide pretreatment suppressed IFN-γ + LPS-induced M1 polarization and promoted the expression of M2-type markers, upregulated the expression of ABCA1, ABCG1, PPARγ, and LXRα, and increased levels of histone H3K27ac. Mechanistic studies revealed that silencing ABCA1 or LXRα reversed the liraglutide-induced increase in H3K27ac and M2 polarization. Acetyl-CoA supplementation partially restored the macrophage polarization phenotype following ABCA1 silencing. ChIP-qPCR results showed that liraglutide significantly enhanced the enrichment of H3K27ac in the promoter regions of M2 polarization genes and cholesterol metabolism genes. Co-culture experiments demonstrated that liraglutide-reprogrammed macrophages significantly promoted adipocyte thermogenic gene expression, increased mitochondrial membrane potential-dependent staining intensity, and enhanced ATPase activity via paracrine signaling, an effect that was blocked by silencing ABCA1 or LXRα. This study demonstrates that liraglutide activates the ABCA1/LXRα-mediated cholesterol metabolism pathway, upregulates histone H3K27ac modification, and drives macrophage M2 polarization, which in turn induces adipocyte lipid accumulation and mitochondrial metabolic activation via paracrine signaling. These findings provide a new molecular mechanism for the anti-inflammatory and metabolic-improving effects of liraglutide, and also offers a potential epigenetic target for the treatment of O&T2DM.
