Author:
Wang Zhaoquan,Lipshutz Allie,Liu Zong-Lin,Trzeciak Alissa J.,Miranda Isabella C.,Martínez de la Torre Celia,Schild Tanya,Lazarov Tomi,Rojas Waleska Saitz,Saavedra Pedro H. V.,Romero-Pichardo Jesús E.,Baako Ann,Geissmann Frederic,Faraco Giuseppe,Gan Li,Etchegaray Jon Iker,Lucas Christopher D.,Parkhurst Christopher N.,Zeng Melody Y.,Keshari Kayvan R.,Perry Justin S. A.
Abstract
AbstractDespite the success of fructose as a low-cost food additive, recent epidemiological evidence suggests that high fructose consumption by pregnant mothers or during adolescence is associated with disrupted neurodevelopment1–7. An essential step in appropriate mammalian neurodevelopment is the synaptic pruning and elimination of newly-formed neurons by microglia, the central nervous system’s (CNS) resident professional phagocyte8–10. Whether early life high fructose consumption affects microglia function and if this directly impacts neurodevelopment remains unknown. Here, we show that both offspring born to dams fed a high fructose diet and neonates exposed to high fructose exhibit decreased microglial density, increased uncleared apoptotic cells, and decreased synaptic pruningin vivo. Importantly, deletion of the high affinity fructose transporter SLC2A5 (GLUT5) in neonates completely reversed microglia dysfunction, suggesting that high fructose directly affects neonatal development. Mechanistically, we found that high fructose treatment of both mouse and human microglia suppresses synaptic pruning and phagocytosis capacity which is fully reversed in GLUT5-deficient microglia. Using a combination ofin vivoandin vitronuclear magnetic resonance- and mass spectrometry-based fructose tracing, we found that high fructose drives significant GLUT5-dependent fructose uptake and catabolism, rewiring microglia metabolism towards a hypo-phagocytic state. Importantly, mice exposed to high fructose as neonates exhibited cognitive defects and developed anxiety-like behavior which were rescued in GLUT5-deficient animals. Our findings provide a mechanistic explanation for the epidemiological observation that early life high fructose exposure is associated with increased prevalence of adolescent anxiety disorders.
Publisher
Cold Spring Harbor Laboratory