Isaiah O. Stephens, Lance A. Johnson
Lipid droplets (LDs) are emerging as key regulators of metabolism and inflammation, with their buildup in microglia linked to aging and neurodegeneration. Perilipin-2 (Plin2) is a ubiquitously expressed LD-associated protein that stabilizes lipid stores; in peripheral tissues, its upregulation promotes lipid retention, inflammation, and metabolic dysfunction. Yet, its role in microglia remains unclear. Using CRISPR-engineered Plin2 knockout (KO) BV2 microglia, we examined how Plin2 contributes to lipid accumulation, bioenergetics, and immune function. Compared to wild-type (WT) cells, Plin2 KO microglia showed markedly reduced LD burden under basal and oleic acid-loaded conditions. Functionally, this was linked to enhanced phagocytosis of zymosan particles, even after lipid loading, indicating improved clearance capacity. Transcriptomics revealed genotype-specific responses to amyloid-β (Aβ), especially in mitochondrial metabolism pathways. Seahorse assays confirmed a distinct bioenergetic profile in KO cells, with reduced basal respiration and glycolysis but preserved mitochondrial capacity, increased spare reserve, and a blunted glycolytic response to Aβ. Together, these findings establish Plin2 as a regulator of microglial lipid storage and metabolic state, with its loss reducing lipid buildup, enhancing phagocytosis, and altering Aβ-induced metabolic reprogramming. Targeting Plin2 may represent a strategy to reprogram microglial metabolism and function in aging and neurodegeneration.