Hypothalamic c-FOS labeling after oral allulose and sucrose exposure in mice

Abstract D-Allulose influences feeding and metabolism, but hypothalamic responses to oral exposure remain incompletely understood. We compared water, 10% sucrose and 13% D-allulose using drinking assays, hypothalamic immunofluorescence and peripheral histology in mice. Sucrose showed the highest consumption and lowest accompanying chow intake, without significant differences in bodyweight change. After fluid familiarization and oral challenge, allulose yielded the highest mean c-FOS co-labeling in neuropeptide Y (NPY)-positive cells, with an exploratory overall difference but nonsignificant pairwise comparisons. Spatial analysis suggested greater clustering of c-FOS-positive NPY cells under allulose (unadjusted p = 0.0286, Holm-adjusted p = 0.0571). Exploratory comparisons also showed higher arcuate c-FOS labeling with allulose than sucrose and higher proopiomelanocortin (POMC)-associated co-labeling than water, although regional omnibus tests were nonsignificant. POMC spatial organization and regional glial staining showed no significant differences. First exposure after a 16-hour fast produced no significant difference in ACTH/CLIP-associated c-FOS co-labeling. Computational histology showed greater relative representation of liver nuclei classified as epithelial-like under allulose. These findings characterize consumption patterns and suggest a spatially grouped NPY-associated response to oral allulose that warrants investigation with matched imaging and functional measurements.