Updated project metadata. The influence of metabolic dysfunction on myelin has been well documented, yet whether central nervous system myelin homeostasis contributes to systemic metabolic regulation remains unclear. Here we identify Tmem117, a previously uncharacterized oligodendrocyte-enriched protein, as a critical regulator of this axis. Conditional deletion of Tmem117 in mature oligodendrocytes induces ER stress, broad proteome dysregulation, and demyelination, with myelin disruption leading to sex-specific effects on counterregulatory response, glucose tolerance, and hepatic lipid accumulation. Mechanistically, we provide evidence that Tmem117 modulates the sodium-calcium exchanger NCX1. These findings uncover a reciprocal link between central nervous system myelin integrity and systemic metabolic homeostasis, and position Tmem117 as a potential target for cell-specific modulation of NCX activity.