PLX3397 Reshapes Hepatic Lipid Metabolism Independent of Microglial Depletion

Colony-stimulating factor 1 receptor (CSF1R) inhibitors, such as PLX5622 and PLX3397 (pexidartinib), are widely used for in vivo microglial depletion and for investigating microglial functions and therapeutic potential. Although CSF1R inhibitor-based studies have uncovered important roles for microglia in processes, such as anesthesia, addiction, and obesity, whether the resulting phenotypes reflect microglial depletion alone remains increasingly debated. Our previous work has shown that PLX5622 activates hepatic constitutive androstane receptor (CAR)-dependent xenobiotic metabolism, altering the metabolism of anesthetics and addictive drugs, and amplifying apparent microglial phenotypes. Whether other CSF1R inhibitors, particularly the FDA-approved PLX3397, exert systemic metabolic effects that may influence the interpretation of brain phenotypes remains unknown. Here, we demonstrate that PLX3397 exerts hepatic metabolic effects that are mechanistically distinct from those induced by PLX5622. Although PLX3397 only weakly affects xenobiotic metabolism, it markedly enhances endogenous hepatic lipid metabolism, inducing a fasting-like state characterized by increased lipid utilization and ketogenesis despite the absence of nutrient deprivation. By uncovering previously unrecognized peripheral effects of PLX3397, our findings identify brain-periphery interactions as a potential source of confounding in studies of microglial function. These results suggest that systemic metabolic effects should be carefully considered when interpreting neural or behavioral phenotypes in pharmacological microglia depletion paradigms.