D-allulose, a rare sugar sweetener, maintained weight loss for 10 days in obese mice while oral semaglutide showed rebound weight gain after day 3, despite both initially reducing weight equally. The key difference: D-allulose activated both vagal nerve pathways and hypothalamic neurons, while semaglutide worked only through brain mechanisms. Both compounds equally improved grip strength, suggesting preserved muscle function during weight loss. This finding challenges the assumption that newer pharmaceutical GLP-1 receptor agonists represent the pinnacle of weight management. D-allulose's dual-pathway approach—stimulating endogenous GLP-1 release peripherally while directly affecting hypothalamic appetite centers—may offer superior long-term weight control compared to centrally-acting drugs alone. The practical implications are substantial: a naturally-occurring, zero-calorie sugar could potentially outperform expensive injectable diabetes medications for sustained weight loss. However, this remains mouse research with artificial feeding conditions. The real test will be whether D-allulose's promising dual-mechanism approach translates to human studies, particularly regarding dosing, safety, and real-world dietary compliance compared to prescription alternatives.