Departments of Medicine and Physiology, Gastrointestinal Diseases Research Unit (GIDRU) Wing, Kingston General Hospital, 76 Stuart Street, Kingston, Ontario, Canada K7L2V7.
J Physiol. 2011 Jun 1;589(Pt 11):2857-70. doi: 10.1113/jphysiol.2010.204594. Epub 2011 Mar 21.
Gastrointestinal vagal afferents transmit satiety signals to the brain via both chemical and mechanical mechanisms. There is indirect evidence that these signals may be attenuated in obesity. We hypothesized that responses to satiety mediators and distension of the gut would be attenuated after induction of diet induced obesity. Obesity was induced by feeding a high fat diet (60% kcal from fat). Low fat fed mice (10% kcal from fat) served as a control. High fat fed mice were obese, with increased visceral fat, but were not hyperglycaemic. Recordings from jejunal afferents demonstrated attenuated responses to the satiety mediators cholecystokinin (CCK, 100 nm) and 5-hydroxytryptamine (5-HT, 10 μm), as was the response to low intensity jejunal distension, while responses to higher distension pressures were preserved. We performed whole cell patch clamp recordings on nodose ganglion neurons, both unlabelled, and those labelled by fast blue injection into the wall of the jejunum. The cell membrane of both labelled and unlabelled nodose ganglion neurons was less excitable in HFF mice, with an elevated rheobase and decreased number of action potentials at twice rheobase. Input resistance of HFF neurons was also significantly decreased. Calcium imaging experiments revealed reduced proportion of nodose ganglion neurons responding to CCK and 5-HT in obese mice. These results demonstrate a marked reduction in afferent sensitivity to satiety related stimuli after a chronic high fat diet. A major mechanism underlying this change is reduced excitability of the neuronal cell membrane. This may explain the development of hyperphagia when a high fat diet is consumed. Improving sensitivity of gastrointestinal afferent nerves may prove useful to limit food intake in obesity.
胃肠道迷走传入纤维通过化学和机械机制将饱腹感信号传递到大脑。有间接证据表明，这些信号在肥胖症中可能会减弱。我们假设，在诱导饮食诱导肥胖后，对饱腹感介质的反应和肠道扩张会减弱。通过喂食高脂肪饮食（脂肪热量的 60%）来诱导肥胖。低脂喂养的小鼠（脂肪热量的 10%）作为对照。高脂肪喂养的小鼠肥胖，内脏脂肪增加，但血糖不升高。空肠传入纤维的记录显示，对饱腹感介质胆囊收缩素（CCK，100nm）和 5-羟色胺（5-HT，10μm）的反应减弱，对低强度空肠扩张的反应也减弱，而对较高扩张压力的反应保持不变。我们对迷走神经节神经元进行了全细胞膜片钳记录，包括未标记的和通过快速蓝注射到空肠壁标记的神经元。在 HFF 小鼠中，无论是未标记的还是通过快速蓝注射到空肠壁标记的神经元，细胞膜的兴奋性都降低，阈强度升高，两倍阈强度时的动作电位数量减少。HFF 神经元的输入电阻也显著降低。钙成像实验表明，肥胖小鼠对 CCK 和 5-HT 反应的迷走神经节神经元比例减少。这些结果表明，慢性高脂肪饮食后，传入纤维对饱腹感相关刺激的敏感性明显降低。这种变化的主要机制是神经元细胞膜兴奋性降低。这可能解释了高脂饮食时食欲增加的发展。改善胃肠道传入神经的敏感性可能有助于限制肥胖症的食物摄入。
