Targeted activation of microglial PPARdelta reprograms immunometabolism and enhances insulin sensitivity in diet-induced obesity.

Microglia play a crucial role in maintaining neuronal health through phagocytosis, a function that becomes compromised during diet-induced obesity and is associated with altered lipid metabolism. Previous research demonstrated that disrupting lipid metabolism in microglia, such as through lipoprotein lipase deficiency, impairs their phagocytic function and exacerbates obesity, glucose dysregulation, and hypothalamic neuron dysfunction. This study investigated whether enhancing lipid metabolism via peroxisome proliferator-activated receptor delta (PPAR{delta}) activation could counteract obesity-related metabolic disturbances. Thermal proteome profiling identified GW0742 as the most potent PPAR{delta} ligand among those tested. GW0742 enhanced microglial phagocytosis, reduced inflammation, and shifted energy metabolism towards glycolysis over oxidative phosphorylation. Targeted delivery of GW0742 using nanoparticles (NPs-GW0742) to microglia in the mediobasal hypothalamus of obese rats significantly improved insulin sensitivity without affecting body weight or food intake. Enhanced microglial activation was evidenced by increased soma size and coverage. These findings underscore the importance of microglial lipid metabolism in systemic glucose regulation and highlight the potential of PPAR{delta}-targeted therapies to mitigate hypothalamic inflammation and improve metabolic health in obesity.