A vagal sensory–hypothalamic oxytocin–brown adipose tissue pathway mediates cholecystokinin-induced thermogenesis
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Thermoregulation is essential for survival in homeothermic animals. Vagal sensory nerves are well known to detect visceral signals and regulate physiological functions, including feeding, metabolism and immunity. However, their role in thermoregulation remains poorly understood. Cholecystokinin (CCK), a gut hormone released postprandially, activates vagal sensory nerves via CCK-A receptors (CCK-AR). Exogenous CCK has been reported to induce thermogenesis in the intrascapular brown adipose tissue (iBAT), but the involvement of vagal sensory nerves and the central neural mechanisms that mediate this effect are not fully understood. In this study, we assessed the thermogenic effect of intraperitoneally (I.P.) administered CCK-8 and investigated the underlying autonomic reflex pathways. I.P. CCK-8 transiently and dose-dependently increased rectal temperature. This response was significantly attenuated by pharmacological blockade of CCK-AR, subdiaphragmatic vagotomy, or knockdown of CCK-AR primarily targeting in 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 intracerebroventricular administration of an oxytocin receptor (OXTR) antagonist attenuated the thermogenic response. These findings demonstrate, for the first time, the full neural circuitry underlying CCK-induced thermogenesis by delineating its afferent input (CCK-AR-expressing vagal sensory neurons), central integrative hub (PVH OXT neurons and OXTR signaling), and 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.
Key points summary
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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.
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This study reveals for the first time the full autonomic reflex pathways underlying thermogenic effect of the gut hormone cholecystokinin (CCK), comprising afferent input (CCK-A receptor-expressing vagal afferents), a central integrative hub (oxytocin neurons in the hypothalamic paraventricular nucleus; PVH OXT neurons), and efferent output (intrascapular brown adipose tissue via sympathetic nerves).
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Both CCK-A receptors-expressing vagal afferents and sympathetic nerves innervating brown adipose tissue are required for thermogenesis induced by exogenous CCK-8.
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Activation of PVH OXT neurons by CCK-8 is critically involved in mediating this thermogenic effect.
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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.
