The unanticipated role of the glial-associated glucose-6-phosphatase system in brain homeostasis

The glucose-6-phosphatase (G6Pase) system is a multiprotein complex within the endoplasmic reticulum that enables glucose export during high energy demand. Although traditionally studied in peripheral tissues such as the liver, recent studies highlight its relevance in the central nervous system, particularly in astrocytes and specialized glial cells called tanycytes. This review explores emerging functions of the G6Pase system in cerebral glial cells and its putative role in the regulation of brain bioenergetics and energy balance. In astrocytes, G6Pase expression supports glucose uptake, ATP production, and endoplasmic reticulum Ca2+ accumulation, contributing to cognitive processes and the counterregulatory response to hypoglycemia. In tanycytes, G6Pase is essential for promoting food intake and maintaining body weight. Collectively, these findings emphasize the importance of the G6Pase system in sustaining brain homeostasis.