Tas2r108 mediates ligand-specific bitter sensitivity and modulates longevity and metabolic health in mice

Purpose: This study aims to elucidate the physiological functions of the type 2 taste receptor 108 (Tas2r108), highly expressed in the tongue and exocrine tissues, focusing on its role in bitter taste perception, metabolic homeostasis, and longevity.Materials and Methods: To identify specific ligands, calcium imaging was performed using CHO-K1 cells transfected with Tas2r108 and Gα16gust44. For in vivo functional analysis, a Tas2r108 knock-out (Tas2r108-/-) mouse model was generated using CRISPR/Cas9. Sensory sensitivity was evaluated through two-bottle preference tests, and long-term physiological monitoring assessed body weight, blood pressure, glucose levels, and plasma leptin concentrations.Results: In vitro assays identified cycloheximide as a primary and potent ligand for Tas2r108 compared to denatonium. In behavioral tests, Tas2r108-/- mice showed a significant reduction in bitter sensitivity to cycloheximide, demonstrating this receptor's essential role in detecting specific bitter ligands. Long-term monitoring revealed that Tas2r108 deficiency significantly extends the average lifespan of mice. While no differences were observed in blood pressure, glucose, or total food intake, Tas2r108-/- mice exhibited greater weight gain during adulthood. Notably, plasma leptin levels were higher in the Tas2r108-/- group, correlating with this period of significant weight gain.Conclusion: These findings demonstrate that Tas2r108 plays a dual role in mediating ligand-specific bitter taste detection and regulating metabolic health and longevity. The results suggest that Tas2r108 may modulate systemic homeostasis through the leptin signaling pathway, identifying it as a potential target for research into aging and metabolic regulation.