Tirzepatide engages a brain-brown adipose tissue axis to promote body weight loss independent of appetite suppression

Abstract Tirzepatide, a dual GIP/GLP-1 receptor agonist, produces greater weight loss than semaglutide, but the neural basis of this difference remains unclear. Here we identify, in mice, a tirzepatide-preferential brain–brown adipose tissue (BAT) pathway that promotes weight loss independent of appetite suppression. Located outside the blood–brain barrier, the area postrema (AP) is directly accessible to circulating tirzepatide. Tirzepatide-responsive AP neurons projecting to the dorsal motor nucleus of the vagus (DMV) provide glutamatergic input to raphe pallidus (RPa)-projecting DMV neurons, thereby recruiting an AP→DMV→RPa circuit that drives BAT thermogenesis. Inhibiting RPa neurons, DMV→RPa projections or AP glutamatergic neurons suppresses tirzepatide-induced BAT activation and attenuates weight loss, whereas optogenetic activation of tirzepatide-responsive RPa neurons or DMV→RPa terminals recapitulates these effects. This pathway accounts for approximately 40% of tirzepatide-induced weight loss but is not effectively recruited by semaglutide. Thus, tirzepatide couples appetite suppression with a distinct brainstem thermogenic mechanism, providing a circuit-level basis for its greater anti-obesity efficacy.