Peripheral cholecystokinin promotes thermogenesis via vagal afferent signalling, hypothalamic oxytocin and sympathetic outflow to brown adipose tissue

Abstract Thermoregulation 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 (PVH OXT ). Chemogenetic inhibition of PVH OXT 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 (PVH OXT 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. image Key points Vagal 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. This 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). This 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.