High fructose diet in early life is bad
by Ulrik Larsen
Inspired by a lab member constantly theorizing about HNF1A and the brain, I came across a study on how early-life high fructose exposure affects brain development, focusing on microglia and their glucose transporter (GLUT5/SLC2A5). The authors show that both prenatal and postnatal fructose exposure impairs microglial phagocytosis in neonatal mice, especially in the prefrontal cortex. This leads to an accumulation of uncleared dying neurons, disrupting normal neurodevelopment.
The study identifies GLUT5, a fructose transporter, as the key mediator. While neonatal mice have low intestinal GLUT5 levels compared to GLUT2 (SLC2A2), microglia is the only central nervous system resident cell expressing GLUT5 at this stage, and its expression increases with fructose exposure. Using full-body and microglia-specific GLUT5 knockout mice, the authors demonstrate that the detrimental effects of fructose on microglia and behavior are entirely dependent on microglial GLUT5. This is due to fructose uptake via GLUT5 shifting microglial metabolism toward increased fructose catabolism and reduced phagocytic capacity. In absence of GLUT5 in the microglia, phagocytosis is preserved and behavioral impairments (e.g., anxiety and cognitive deficits) are prevented.
In summary, the study shows that early-life fructose intake impairs neurodevelopment via microglial GLUT5-driven metabolic changes, highlighting the importance of early dietary exposures. One small idea from this study could be if HNF1A causes reduced expression of GLUT2, could it lead to less competition of the fructose, affecting the developing brain? Though, in the context of fructose, GLUT2 is mainly responsible for transporting fructose from the intestinal cells to the blood and not from the food like GLUT5 so…maybe…maybe not.
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Wang Z, Lipshutz A, Martínez de la Torre C, Trzeciak AJ, Liu ZL, Miranda IC, Lazarov T, Codo AC, Romero-Pichardo JE, Nair A, Schild T, Saitz Rojas W, Saavedra PHV, Baako AK, Fadojutimi K, Downey MS, Geissmann F, Faraco G, Gan L, Etchegaray JI, Lucas CD, Tanasova M, Parkhurst CN, Zeng MY, Keshari KR, Perry JSA. Early life high fructose impairs microglial phagocytosis and neurodevelopment Nature. 2025 Jun 11:10.1038/s41586-025-09098-5. doi: 10.1038/s41586-025-09098-5.