On the tongue, the T1R-independent pathway (comprising glucose transporters, including sodium–glucose cotransporter (SGLT1) and the K_ATP channel) detects only sugars, whereas the T1R-dependent (T1R2/T1R3) pathway can broadly sense various sweeteners. Cephalic-phase insulin release, a rapid release of insulin induced by sensory signals in the head after food-related stimuli, reportedly depends on the T1R-independent pathway, and the competitive sweet taste modulators leptin and endocannabinoids may function on these two different sweet taste pathways independently, suggesting independent roles of two oral sugar-detecting pathways in food intake. Here, we examined the effect of adrenomedullin (ADM), a multifunctional regulatory peptide, on sugar sensing in mice since it affects the expression of SGLT1 in rat enterocytes. We found that ADM receptor components were expressed in T1R3-positive taste cells. Analyses of chorda tympani (CT) nerve responses revealed that ADM enhanced responses to sugars but not to artificial sweeteners and other tastants. Moreover, ADM increased the apical uptake of a fluorescent D-glucose derivative into taste cells and SGLT1 mRNA expression in taste buds. These results suggest that the T1R-independent sweet taste pathway in mouse taste cells is a peripheral target of ADM, and the specific enhancement of gustatory nerve responses to sugars by ADM may contribute to caloric sensing and food intake.

Sodium ascorbate (AsA-Na) is widely used as a source of vitamin C. However, the mechanisms regulating voluntary intake across different concentrations and nutritional states remain poorly understood. Therefore, we examined behavioral and neural responses to AsA-Na in osteogenic disorder Shionogi (ODS) od/od rats, which lack endogenous vitamin C synthesis. Two-bottle choice tests were used to evaluate long-term behavioral responses, and the contribution of epithelial sodium channel (ENaC)-dependent taste signaling was examined using amiloride. In parallel, chorda tympani (CT) nerve responses were recorded with and without amiloride treatment. AsA-Na consistently showed lower preference scores than NaCl across concentrations. At 30 to 100 mM, the preference for AsA-Na was lower than that for NaCl but significantly higher than that for AsA. Lick responses to AsA-Na were comparable to those for NaCl and were enhanced under vitamin C–deficient conditions. Although the 48-h intake of 100 mM AsA-Na remained low under all conditions, the intake of 10 mM AsA-Na increased selectively during the re-intake phase. Notably, amiloride strongly suppressed CT nerve responses to AsA-Na. While amiloride significantly reduced NaCl preference and intake, it had no effect on AsA-Na preference or sustained intake. These results support a dissociation between ENaC-mediated peripheral sensory signaling and long-term ingestive behavior. Although AsA-Na is detected via sodium taste pathways, this sensory input alone cannot account for sustained intake. Instead, intake is likely influenced by post-ingestive mechanisms in a concentration- and state-dependent manner. These findings suggest an important contribution of internal nutritional signals in shaping chemosensory-driven behavior.