We evaluated denatonium acetate (DA), a gut-restricted TAS2R agonist, across preclinical and clinical settings, and explored its combination with sitagliptin (a dipeptidyl peptidase-4 [DPP-4] inhibitor).<h4>Methods</h4>In mice transitioned to high-fat diet (HFD) or established with diet-induced obesity (DIO), we tested oral DA (20-80 mg/kg twice daily or 75 mg/kg once daily), a sitagliptin-formulated HFD, the combination, and subcutaneous tirzepatide, including a post-tirzepatide discontinuation phase, to assess weight trajectories and metabolic benefits. The gene discussed is DPP4; the disease is obesity disorder.