Abstract
The cholecystokinin (CCK) induced satiety signaling of vagal afferents is suppressed in diet‐induced obese mice, which contributes to the increased food intake. In this study we tested the hypothesis that a Ca2+‐activated chloride channel (CaCC) mediates the response of normal intestinal vagal afferent nodose neurons to CCK and that excessively high fat diet (HFD) suppresses the channel activation and leads to obesity. We first used Ca2+ imaging techniques and the whole cell patch‐clamp on cultured nodose ganglia neurons isolated from anesthetized C57/BL6 mice. Application of CCK increased [Ca2+]i in a dose‐dependent manner reaching near maximal level at 10 μM. This dose of CCK also induced a large inward current (36.0±11.0 pA/pF, n=7) that was eliminated with the fast Ca2+ chelator BAPTA (1.0±0.5 pA/pF, n=7). The reversal potential of the current was ~0mV with equal concentration of Cl‐ on both sides of the cell membrane and shifted to a more positive direction after lowering the extracellular [Cl‐]o confirming that it is an outward Cl‐ conductance. Moreover, the CCK‐induced response was reduced significantly from 35.2±3.2 pA/pF in untreated control neurons (n=9) to 13.6±2.0 pA/pF in the presence of niflumic acid (100μM, n=8), a blocker of the CaCC channel (p<0.05). DiI labeled proximal intestinal nodose neurons obtained from control mice responded to CCK with an average current of 24.8±4.9 pA/pF (n=7), whereas the response of labeled neurons from obese mice fed a 60% HFD for 10 weeks was significantly lower at 6.1±2.9 pA/pF (n=7) (p<0.01). Our results demonstrate that a CCK‐sensitive CaCC in proximal intestinal nodose neurons is desensitized in mice fed a high fat diet. This CaCC ionic conductance may be responsible for satiety signaling of vagal afferents and its impairment may contribute to excessive food intake and obesity.Grant Funding Source: Supported by NIH HL 14388
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