ApoE-Dependent Lipid Handling by Median Eminence Microglia Preserves Myelin Integrity and Metabolic Function

Abstract Microglia regulate hypothalamic control of systemic metabolism, but the mechanisms underlying their contribution remain unclear. Here, we identify a distinct apolipoprotein E ( ApoE )⁺ microglial population enriched in the median eminence (ME), a brain region involved in sensing peripheral cues and metabolic regulation. These microglia engage multiple functional programs related to lipid handling, interferon signaling, and stress responses that are differentially regulated within the ME. Consumption of a Western diet (WD) increased interferon signaling and lipid accumulation in ME microglia. Expression of the human APOE4 isoform in mice exacerbated microglial lipid dysregulation, interferon signaling, and impaired ME myelin organization. Deleting APOE in microglia attenuated their ability to couple lipid accumulation to interferon signaling, identifying microglial APOE as a cell-intrinsic determinant of interferon responses. Finally, selective activation of liver X receptor signaling using synthetic HDL nanoparticles restored microglial lipid homeostasis, improved hypothalamic leptin responsiveness, and limited weight gain in WD–fed mice. Together, these findings define an Apoe -dependent regulatory program in ME microglia that is therapeutically targetable and clarify how nutritional stress disrupts hypothalamic control of metabolic homeostasis.