Fructose-induced anxiety

Abstract

The Western diet, which is rich in high-fructose (HF) foods and beverages, has been linked to adverse health outcomes, including neurodevelopmental disorders. In a study published in Nature, Wang et al. show that prenatal or neonatal exposure to HF impairs microglial phagocytic activity in mice. This results in reduced phagocytosis of synaptosomes and apoptotic neurons, which is a key process in healthy brain development. Notably, the number, morphology, and phagocytic function of microglia were preserved in neonatal mice lacking GLUT5, the primary fructose transporter, despite being born to and nursed by HF-fed dams. In vitro, wild-type mouse and human microglia cultured in HF conditions had impaired phagocytosis, but this was not observed in GLUT5-deficient microglia. Further experiments indicated that HF reduced phagocytic function by increasing GLUT5-dependent fructose uptake and conversion to fructose 6-phosphate, thereby altering microglial metabolism toward a non-phagocytic state in part by increasing mitochondrial hexokinase 2 localization. Neonatal HF consumption was associated with impairments in novel-object recognition and fear extinction in adolescent wild-type, but not GLUT5-deficient, mice. These findings suggest that early-life HF exposure disrupts microglial function and might affect neurodevelopment, underscoring the importance of limiting dietary fructose during pregnancy and early life.

Original reference: Nature https://doi.org/10.1038/s41586-025-09098-5 (2025)