Targeted PPARδ activation reprograms microglial immunometabolism and improves insulin sensitivity in HFD-fed rats.

Microglia lipid metabolism plays a crucial role in maintaining immune function and supporting neuronal health. Previous studies have shown that a high-fat diet (HFD) promotes lipid accumulation in microglia, while disruption of lipid uptake and utilization impair neuroimmune competency and accelerate obesity in response to a HFD, highlighting the importance of lipid processing under obesogenic conditions. However, whether enhancing microglial lipid metabolism can restore their immune function and mitigate obesity-associated hypothalamic dysfunction remains unclear. In this study, we investigated whether activation of peroxisome proliferator-activated receptor delta (PPARδ), a key regulator of lipid metabolism, could counteract obesity-related metabolic disturbances. Using thermal proteome profiling, we identified GW0742 as the most potent PPARδ agonist among those tested. Treatment of microglial cells in vitro with GW0742 enhanced phagocytosis, reduced inflammation, and improved microglial metabolic flexibility. To assess therapeutic potential in vivo, we selectively delivering GW0742 to mediobasal hypothalamic microglia in HFD-fed rats using polymeric nanoparticles (NPs-GW0742). This targeted intervention reprogrammed microglial activity and improved insulin sensitivity without affecting body weight or food intake, suggesting a direct central metabolic benefit. Our findings highlight the therapeutic potential of targeting microglial lipid metabolism to improve metabolic health in obesity.