3034-LB: Microglial GLUT1 Regulates Hypothalamic Glucose Sensing and Systemic Glucose Homeostasis

Introduction and Objective: Glucose is essential for brain homeostasis, and microglia, the brain's resident immune cells, depend on the glucose transporter GLUT1 for glucose uptake. However, whether microglial glucose metabolism influences neuronal function and systemic metabolic regulation remains unknown. Methods: Here, we generated microglial-specific GLUT1 knockout mice (Cx3cr1-CreER::Glut1flox/flox) to investigate the role of microglial GLUT1 in hypothalamic glucose sensing and whole-body glucose homeostasis under normal chow and high-fat diet (HFD) conditions. Results: Under chow diet, GLUT1 deletion increased microglial density in the arcuate nucleus of the hypothalamus (ARH) and elevated inflammatory marker co-localization, particularly in females. This microglial dysregulation impaired neuronal glucose sensing, as reflected by reduced glucose-induced cFos activation and disrupted microglial electrophysiological responses to glucose fluctuations in the ARH. Functionally, GLUT1 ablation blunted the glucose-induced suppression of food intake and improved glucose tolerance in males without affecting baseline metabolism. Under HFD conditions, microglial GLUT1 deletion exacerbated hypothalamic inflammation, evidenced by increased inflammatory gene expression and microglial density. This led to systemic glucose dysregulation with pronounced sex-dependent effects: males exhibited impaired glucose tolerance and enhanced hepatic gluconeogenesis, whereas females showed compensatory mechanisms, suggesting sex-specific metabolic resilience. Conclusion: Together, our findings demonstrate that microglial glucose metabolism via GLUT1 is critical for hypothalamic regulation of peripheral glucose homeostasis, particularly during metabolic stress. Disclosure P. Xu: None. Y. He: None. X. Yang: None. Funding National Institutes of Health (DK123098, DK129548)