Acetylated starch promotes satiety by inhibiting hypothalamic agouti-related peptide and neuropeptide Y neurons.

Acetylated starch (AS) has shown promise in promoting satiety, yet the pathways linking its intake to central hypothalamic control remain unclear. An integrated multi-omics approach was employed in mice, combining untargeted serum and fecal metabolomics with hypothalamic transcriptomics, qPCR, and immunofluorescence. AS lowered food intake and reduced immunofluorescent signals from orexigenic agouti-related peptide (AgRP) and neuropeptide Y (NPY) neurons in the arcuate nucleus. The levels of D-phenylalanine, fructose-6-phosphate, and deoxyadenosine in both circulation and the hindgut. The higher OGT and lower Foxo1 transcript levels, along with changes in insulin/leptin- and inflammatory-pathway genes (e.g., IRS/JAK up; TAK1/TRAF6/JNK1 down). These findings are consistent with a model in which AS modulates gut-derived metabolites and hypothalamic signaling, potentially enhancing cholecystokinin pathways (via D-phenylalanine) and hexosamine flux (via fructose-6-phosphate) that converge to suppress AgRP/NPY activity and promote satiety. This study provides new insights into the functional role of AS in the regulation of satiety.