Anxiety-like behavior in adolescents caused by high fructose diets is likely due to its damaging effects on brain immune cells called microglia. These microglia are then unable to perform their job of clearing dead neurons in the brain, crucial for brain development. Excessive consumption of fructose, especially during early life, impairs brain immune cells called microglia Fructose is a common sugar found in many of our food and drinks. The rise of excessive consumption of fructose in our diets is known to contribute to metabolic diseases such as obesity and diabetes. Recent studies also suggest its links to disrupted brain development, especially when consumed during pregnancy, early life or adolescence. Healthy brain development is a carefully controlled process. Neurons multiply and form new connections with each other, whilst unneeded neurons die and are engulfed and cleared by immune cells in the brain called microglia. We know that disrupted removal of these dying neurons can have catastrophic consequences on brain development in animals, including development of anxiety-like behaviours. Chronic excessive consumption of fructose has occurred in tandem with an explosion of mood and anxiety disorders, especially in adolescents. Our findings provide a direct explanation for the observation that early life high fructose exposure is associated with increased prevalence of adolescent anxiety disorders. Dr Chris Lucas RR Group Leader and one of the paper’s authors High fructose diet impairs clearing of dying cellsIRR Group Leader Chris Lucas working with colleagues from New York and St. Louis, found that if you gave a high fructose diet to pregnant mice, their offspring’s microglia were less able to clear dying neuron cells. The same was true for young mice fed extra fructose. Fructose transporters responsible for microglia impairmentWhy are microglia less able to clear dying cells? The scientists found that these microglia uniquely display many fructose transporters on their surface, which makes them especially sensitive to fructose levels. Young mice exposed to high fructose developed anxiety-like behavior as adolescents. Importantly, when the researchers removed these specific transporters, this anxiety-like behaviour was not seen. This study shows that it is the fructose transporters on microglia that make these microglia especially sensitive to high fructose levels, which then interferes with the microglial’s job of clearing dying cells which disrupts brain development. Brain immune cells called microglia (green), with internalised/cleared dead cell neuron-derived material (red). There is reduced dead cell clearance with high fructose that is then rescued by removal of the fructose transporters. While the scientists mostly studied brain development and consequences of fructose for adolescent animals, whether these impacts also extend into later life are yet to be studied. Similarly, microglia and their ability to clear dying cells have been implicated in several human neurodegenerative diseases that usually impact in later life. Whether fructose and its transporter are implicated in these conditions will require ongoing investigation. This work was supported by the NIH, Pew Biomedical Scholars and MSKCC Cancer Center.Read the full paper in ‘Nature’Lucas research groupPerry research group Tags CIR Publication date 11 Jun, 2025
