Leptin and CCK modulate complementary background conductances to depolarize cultured nodose neurons

Abstract

-We have previously reported that intraceliac infusion of leptin induces a reduction of meal size that depends on intact vagal afferents. This effect of leptin is enhanced in the presence of cholecystokinin (CCK). The mechanisms by which leptin and CCK activate vagal afferent neurons are not known. In the present study, we have begun to address this question by using patch-clamp electrophysiological techniques to examine the mechanisms by which leptin and CCK activate cultured vagal afferents from adult rat nodose ganglia. We found that leptin depolarized 41 (60%) of 68 neurons. The magnitude of membrane depolarization was dependent on leptin concentration and occurred in both capsaicin-sensitive and capsaicin-insensitive neurons. We also found that a majority (16 of 22; 73%) of nodose neurons activated by leptin were also sensitive to CCK. CCK-induced depolarization was primarily associated with the increase of an inward current (11 of 12), whereas leptin induced multiple changes in background conductances through a decrease in an outward current (7 of 13), an increase in an inward current (3 of 13), or both (3 of 13). However, further isolation of background currents by recording in solutions that contained only sodium or only potassium revealed that both leptin and CCK were capable of increasing a sodium-dependent conductance or inhibiting a potassium-dependent conductance. Our results support the hypothesis that vagal afferents are a point of convergence and integration of leptin and CCK signaling for control of food intake and suggest multiple ionic mechanisms by which leptin and CCK activate vagal afferent neurons.cholecystokinin; vagal afferents; capsaicin; satiation THE ADIPOKINE HORMONE LEPTIN and the intestinal peptide cholecystokinin (CCK) have profound effects on food intake and energy expenditure. Leptin is secreted into the systemic blood primarily by white adipose tissue (7,14). When administered exogenously, leptin induces several physiological changes, the most dramatic of which is the rapid loss of body fat (11). CCK, a peptide produced and stored within enteroendocrine I cells of the upper small intestine, is secreted in response to fat or protein in the intestinal lumen (12). When administered exogenously or released endogenously, CCK decreases meal size and evokes a behavioral pattern consistent with an enhancement of the satiation process (31). During the past 10 years, several observations (2,15,18,19) have suggested that leptin and CCK may interact synergistically at multiple levels along the neuroaxis to produce changes in food intake and energy expenditure. Indeed, recent reports from our laboratory and others suggest that such leptin-CCK synergy may even occur at the level of primary vagal afferent neurons.Vagal afferent neurons innervate a majority of the abdominal viscera and express both leptin and CCK receptors (4 -6, 17). It is well established that satiation produced by peripheral CCK involves activation of vagal afferent neurons (10,21,29,30,32). On the other hand, many effects ...

Synergistic Interaction between Leptin and Cholecystokinin in the Rat Nodose Ganglia Is Mediated by PI3K and STAT3 Signaling Pathways

“…In this study, we delineated the intracellular mechanisms by which CCK-8 interacts with leptin to enhance NG excitation through STAT3 signaling. STAT3 usually acts by stimulating the transcription of target genes (33), but the rapid electrophysiological effects that were observed in this study and that have been reported by others (24,29,34) are not likely to be explained by STAT3-mediated transcription. It is possible that STAT3 may be involved in modifying the activity of channels or receptors.…”

Low-affinity CCK-A receptors are coexpressed with leptin receptors in rat nodose ganglia: implications for leptin as a regulator of short-term satiety

“…Furthermore, leptin rapidly increased cytosolic calcium in vagal afferent neurons and this signal was synergistically enhanced by the presence of CCK (29). Using patch-clamp electrophysiological studies, these investigators demonstrated that leptin reversibly depolarized a subpopulation of cultured nodose neurons, many of which were also activated by CCK (31). These function studies suggest that vagal afferent neurons are potential targets for leptin-CCK interaction for the control of satiety.…”

Effects of brain stem cholecystokinin-8s on gastric tone and esophageal-gastric reflex

“…Much of the vagal NANC inhibitory effect on the stomach is mediated by the release of nitric oxide onto gastric smooth muscle (1,10,24,37,41,44,45,68). Perfusion with CCK-8s induces an excitation in most neurons, including identified gastrointestinal-projecting DMV neurons (4,7,13,23,38,47,48,65,66,75,79). The excitatory effects of CCK-8s on vagal motoneurons imply that the gastroinhibition induced by brain stem apposition of CCK-8s is likely due to activation of the NANC vagal pathway rather than withdrawal of the vagal cholinergic pathway.…”