Development of a cell-based sweet perception model to study the metabolic effect of different sweeteners.

Sweet taste perception is primarily mediated by the T1R2/T1R3 receptor complex and plays a key role in dietary preference and human health. There is a growing significance in studying the relationship between sweet taste perception and metabolic responses. This study aimed to investigate metabolites changes associated with transient stimulation by different sweeteners (sucrose, neotame and sucralose) by a non-targeted metabolomic approach. The differential metabolite analysis and pathway enrichment revealed that different sweeteners activated distinct metabolic pathways and further impacted on cellular activity. As a nutritive sweetener, the transient stimulation by sucrose led to changes in numerous key intermediates in the tricarboxylic acid cycle within cells, suggesting the role of nutritive sweeteners in regulation of cellular energy metabolism. In contrast, many lipids were affected by neotame and sucralose transient stimulation, indicating that these non-nutritive sweeteners could impact cellular signaling and energy homeostasis. Additionally, we can effectively differentiate the metabolic profiles of these three sweeteners within 95% of the confidence interval through partial least squares-discriminant analysis. These findings offer insights into the diverse cellular metabolic responses induced by various sweeteners and provide a deeper understanding of receptor-mediated intracellular signaling. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-41678-x.