CO-TARGETING THE ENDOCANNABINOID AND MELATONINERGIC SYSTEMS MODULATES LIPID DYNAMICS IN MICROGLIA

Lipids act as signaling molecules, energy substrates and inflammatory mediators and are deeply linked to phagocytosis, inflammation and tissue repair processes. Dysregulated lipid handling in microglia/macrophages contributes to chronic inflammation, neurodegeneration and defective regenerative responses. The identification of therapeutic strategies capable of regulating lipid droplets (LDs) metabolism and turnover in microglia/macrophages has been proposed as a promising approach in various neuroinflammatory conditions such as Alzheimer's disease and multiple sclerosis. The endocannabinoid and melatoninergic systems play critical roles in orchestrating lipid metabolism and shaping microglial responses following CNS injury. We previously showed that UCM1341, a dual-acting compound enhancing both endocannabinoid and melatoninergic signaling, exerted neuroprotective actions against the neuroinflammatory damage, and polarized microglia/macrophages toward an anti-inflammatory phenotype. However, how these systems influence lipid dynamics in microglia remains unclear.
By means of confocal and live-imaging studies, we characterized the time-dependent kinetics of LDs dynamics in BV2 microglia exposed to UCM1341, or reference compounds, melatonin or URB597 (FAAH inhibitor). Then, we examined the effects of these compounds on LDs catabolism and found that UCM1341 enhanced lipophagy and support lipid catabolism when lipophagy was inhibited, highlighting the added benefit of dual targeting on microglial lipid clearance. Notably, UCM1341-driven lipid turnover in microglia involves PPAR-alpha receptor and SIRT1-dependent epigenetic mechanisms.
Collectively, our results suggest that dual enhancement of the endocannabinoid and melatoninergic systems modulate lipid dynamics in microglia.