PLX3397-Induced Microglial Ablation Alters Adipose Tissue Accumulation in a Male–Female-Dependent Manner Under High-Energy-Diet Feeding

Background: Diet-induced obesity (DIO) is increasingly linked to microglial proliferation in the central nervous system, yet the causal role of microglia in metabolic and behavioral changes remains unclear. Methods: Here, we investigated the effects of microglial suppression using the CSF-1R antagonist PLX 3397 (Pexidartinib; PLX) on body weight, adiposity, and sucrose preference in lean and DIO male and female rats. Microglial activation was quantified in the hypothalamus and nucleus tractus solitarius (NTS). Results: PLX administered during initial high-energy-diet (HED) exposure produced sex-specific effects: body weight increased in males but decreased in females. In male DIO rats, PLX+HED reduced body fat percentage without altering total weight. PLX treatment did not significantly alter body weight, food intake, or glucose tolerance in females. Hypothalamic microglial suppression was more extensive in males, whereas NTS suppression was similar across sexes. PLX also reversed HED-induced reductions in low-concentration sucrose preference in males. Substantial individual variability was observed in both susceptibility to DIO and responsiveness to PLX. Conclusions: These findings reveal a clear sexual dimorphism in microglial responses to HED, with females showing relative protection and males’ greater vulnerability. Overall, the results underscore the importance of accounting for sex differences in the design and application of microglia-targeted interventions.