Early life high fructose impairs microglial phagocytosis and neurodevelopment

Authors

Zhaoquan Wang, Memorial Sloan-Kettering Cancer Center
Allie Lipshutz, Memorial Sloan-Kettering Cancer Center
Celia Martínez de la Torre, Memorial Sloan-Kettering Cancer Center
Alissa J. Trzeciak, Memorial Sloan-Kettering Cancer Center
Zong Lin Liu, Memorial Sloan-Kettering Cancer Center
Isabella C. Miranda, Weill Cornell Medicine
Tomi Lazarov, Memorial Sloan-Kettering Cancer Center
Ana C. Codo, Memorial Sloan-Kettering Cancer Center
Jesús E. Romero-Pichardo, Memorial Sloan-Kettering Cancer Center
Achuth Nair, Memorial Sloan-Kettering Cancer Center
Tanya Schild, Memorial Sloan-Kettering Cancer Center
Waleska Saitz Rojas, Memorial Sloan-Kettering Cancer Center
Pedro H.V. Saavedra, Memorial Sloan-Kettering Cancer Center
Ann K. Baako, Weill Cornell Medicine
Kelvin Fadojutimi, Memorial Sloan-Kettering Cancer Center
Michael S. Downey, Memorial Sloan-Kettering Cancer Center
Frederic Geissmann, Memorial Sloan-Kettering Cancer Center
Giuseppe Faraco, Weill Cornell Medicine Feil Family Brain & Mind Research Institute
Li Gan, Weill Cornell Medicine Feil Family Brain & Mind Research Institute
Jon Iker Etchegaray, Washington University School of Medicine in St. Louis
Christopher D. Lucas, MRC Centre for Inflammation Research
Marina Tanasova, Michigan Technological University
Christopher N. Parkhurst, Memorial Sloan-Kettering Cancer Center
Melody Y. Zeng, Weill Cornell Medicine
Kayvan R. Keshari, Memorial Sloan-Kettering Cancer Center
Justin S.A. Perry, Memorial Sloan-Kettering Cancer Center

Document Type

Article

Publication Date

1-1-2025

Abstract

Despite the success of fructose as a low-cost food additive, epidemiological evidence suggests that high fructose consumption during pregnancy or adolescence is associated with disrupted neurodevelopment1, 2–3. An essential step in appropriate mammalian neurodevelopment is the phagocytic elimination of newly formed neurons by microglia, the resident professional phagocyte of the central nervous system4. Whether high fructose consumption in early life affects microglial phagocytosis and whether this directly affects neurodevelopment remains unknown. Here we show that offspring born to female mice fed a high-fructose diet and neonates exposed to high fructose exhibit decreased phagocytic activity in vivo. Notably, deletion of the high-affinity fructose transporter GLUT5 (also known as SLC2A5) in neonatal microglia completely reversed microglia phagocytic dysfunction, suggesting that high fructose directly affects neonatal development by suppressing microglial phagocytosis. Mechanistically, we found that high-fructose treatment of mouse and human microglia suppresses phagocytosis capacity, which is rescued in GLUT5-deficient microglia. Additionally, we found that high fructose drives significant GLUT5-dependent fructose uptake and catabolism to fructose 6-phosphate, rewiring microglial metabolism towards a hypo-phagocytic state in part by enforcing mitochondrial localization of the enzyme hexokinase 2. Mice exposed to high fructose as neonates develop anxiety-like behaviour as adolescents—an effect that is rescued in GLUT5-deficient mice. Our findings provide a mechanistic explanation for the epidemiological observation that high-fructose exposure during early life is associated with increased prevalence of adolescent anxiety disorders.

Publication Title

Nature

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