Microglial immunometabolism in obesity

Microglia, the resident immune cells of the central nervous system, play essential roles in brain development and homeostasis. Their functions are highly dynamic and closely regulated by metabolic and circadian cues. Disruption of these regulatory systems, for example through high-fat diets and irregular feeding patterns, contributes to neuroinflammation and metabolic dysfunction. This thesis investigates how circadian rhythms, lipid metabolism, and dietary interventions interact to shape microglial function and central nervous system health.
Using rodent models, we examined the effects of time-restricted feeding and dietary composition on microglial rhythmicity, immunometabolism, and neuroinflammatory responses. We demonstrate that aligning food intake with the active phase improves metabolic outcomes and partially restores microglial circadian gene expression, while mistimed feeding exacerbates dysfunction. Time-restricted feeding also reduces spinal neuroinflammation and preserves neuron-glia interactions under high-fat diet conditions, although persistent metabolic memory limits full recovery.
In parallel, we explored the role of lipid metabolism in microglial homeostasis. Targeted activation of peroxisome proliferator-activated receptor delta using nanoparticle-based delivery enhanced microglial phagocytosis and improved systemic insulin sensitivity in obese animals. Furthermore, genetic disruption of lipid mobilization revealed sex- and age-dependent vulnerabilities in neuronal lipid handling, microglial function, and glymphatic clearance.
Together, these findings demonstrate that microglial activity is profoundly shaped by temporal and metabolic signals. Modulating feeding rhythms and lipid metabolism represents a promising strategy to mitigate neuroinflammation and metabolic brain disorders, while highlighting the need for personalized approaches across sex and aging.