Semaglutide, a GLP-1R agonist, is widely used for obesity and type 2 diabetes, but its neural mechanisms remain unclear. AgRP neurons regulate energy balance, yet their role in Semaglutide’s effects is unknown. We show that sustained treatment of female mice with Semaglutide leads to activation rather than inhibition of AgRP neurons. Ablation or hypofunction of AgRP neurons through cell-specific knockout of Sirt1 reduces Semaglutide-induced weight loss and impairs its hypoglycemic effects in female mice under Standard Diet. However, acute or chronic exposure to High-Fat Diet makes AgRP neurons dispensable for weight loss, suggesting that neural substrates for the actions of Semaglutide depends on dietary composition. Re-exposure to Standard Diet recovers the necessity for AgRP neurons, underscoring the influence of nutritional status on GLP-1R pathways. Our findings show the necessity for AgRP neurons in sustaining Semaglutide-induced weight loss in female mice on standard diet in vivo .