["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend A vagal sensory–hypothalamic oxytocin–brown adipose tissue (BAT) axis contributes to thermogenesis induced by peripheral cholecystokinin (CCK). i.p. injection of CCK‐8 activates vagal sensory nerves via CCK‐A receptors (CCK‐AR). This afferent signal is relayed through the nucleus tractus solitarius (NTS) to activate oxytocin (OXT) neurons in the paraventricular nucleus of the hypothalamus (PVH). These PVHOXT neurons subsequently stimulate OXT receptor (OXTR)‐expressing neurons in the rostral medullary raphe (rMR). The resulting activation of the sympathetic efferent pathway leads to the stimulation of β3‐adrenergic receptors (β3‐AR) in BAT, inducing non‐shivering thermogenesis. Consequently, CCK‐8 administration increases both core body temperature and whole‐body energy expenditure. This functional gut–brain–fat axis might represent a novel neural mechanism linking postprandial gut signals to metabolic thermoregulation.\n\n\n\n\n\n\n\n\n\nAbstract\nThermoregulation is essential for survival in homeothermic animals. Vagal sensory nerves are well known to detect visceral signals and regulate feeding and metabolic functions, but their role in thermoregulation remains poorly understood. Cholecystokinin (CCK), a gut hormone released postprandially, activates vagal sensory nerves via CCK‐A receptors (CCK‐AR). Although exogenous CCK has been reported to induce thermogenesis in intrascapular brown adipose tissue (iBAT), whether this effect depends on vagal pathways and specific central circuits remains incompletely understood. Here, we assessed the thermogenic effect of i.p. administered CCK‐8 and investigated the underlying autonomic reflex pathways. i.p. CCK‐8 transiently and dose‐dependently increased rectal temperature and oxygen consumption without changing locomotor activity. This response was significantly attenuated by pharmacological blockade of CCK‐AR, subdiaphragmatic vagotomy or knockdown of CCK‐AR primarily targeting vagal sensory neurons. In addition, CCK‐8 activated sympathetic nerve activity via vagal afferents. CCK‐8‐induced thermogenesis was blunted by iBAT sympathectomy or β3‐adrenergic receptor blockade. Furthermore, i.p. CCK‐8 activated oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVHOXT). Chemogenetic inhibition of PVHOXT neurons or oxytocin receptor expressing neurons in the rostral medullary raphe attenuated the thermogenic response. These findings suggest that CCK‐induced thermogenesis involves functional neural components, including the afferent input (CCK‐AR‐expressing vagal afferents), the central integrative hub (PVHOXT neurons and OXTR signalling), and the efferent output (iBAT sympathetic nerves). This study further suggests that CCK‐AR‐expressing vagal sensory neurons may contribute to thermoregulation under physiological conditions in which CCK is endogenously released.\n\n\n\n\n\n\n\n\n\nKey points\n\nVagal sensory nerves, which connect the gut and the brain, play a key role in regulating meal‐related physiology; however, their role in thermoregulation remains incompletely understood.\nThis study reveals that i.p. cholecystokinin (CCK)‐induced thermogenesis involves functional neural components, including the afferent input (CCK‐A receptor‐expressing vagal afferents), the central integrative hub (hypothalamic oxytocin neurons in the paraventricular nucleus and oxytocin receptor‐expressing neurons in the rostral medullary raphe) and the efferent output (sympathetic nerves innervating intrascapular brown adipose tissue).\nThis newly identified gut–brain–fat axis may contribute to part of diet‐induced thermogenesis, and its impairment could be involved in the development of metabolic disorders such as obesity.\n\n\n"]