Impaired intestinal afferent nerve satiety signalling and vagal afferent excitability in diet induced obesity in the mouse
Impaired intestinal afferent nerve satiety signalling and vagal afferent excitability in diet induced obesity in the mouse
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DOI：
10.1113/jphysiol.2010.204594
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发表时间：
2011-06-01
影响因子：
5.5
通讯作者：
Beyak, Michael J.
中科院分区：
文献类型：
--
作者：
Daly, Donna M.;Park, Sung Jin;Beyak, Michael J.
非技术概述已知肥胖是由于能量摄入超过支出。目前尚不清楚的是，人们是如何能够吃超过他们的能量需求。我们发现，在长期食用高脂肪饮食（导致肥胖）后，肠道感觉神经对进餐期间从肠道释放的化学物质（胆囊收缩素和5-羟色胺）以及进餐期间可能发生的肠道扩张的反应较低。这似乎是由于神经细胞兴奋的能力受损。这表明，导致肥胖的不健康饮食导致肠道信号减少，这可能导致食物摄入量增加，并有助于进一步增加体重，或允许维持多余的体重和肥胖。胃肠道迷走神经传入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，这些信号可能在肥胖症中减弱。我们假设，在诱导饮食诱导的肥胖后，对饱腹感介质和肠道扩张的反应会减弱。通过喂食高脂肪饮食（60%千卡来自脂肪）诱导肥胖。低脂肪喂养的小鼠（来自脂肪的10%千卡）作为对照。高脂肪喂养的小鼠肥胖，内脏脂肪增加，但没有高血压。记录从空肠传入表现出衰减的反应，饱食介质胆囊收缩素（CCK，100 nm）和5-羟色胺（5-HT，10 μ m），是低强度的空肠扩张的反应，而较高的扩张压力的反应被保存。我们进行了全细胞膜片钳记录结状神经节神经元，无论是未标记的，和那些标记的快蓝注射到空肠壁。HFF小鼠的标记和未标记的结状神经节神经元的细胞膜兴奋性较低，具有升高的基强度和减少的动作电位数量。HFF神经元的输入电阻也显著降低。钙离子成像实验显示肥胖小鼠结状神经节神经元对CCK和5-HT反应的比例减少。这些结果表明，在慢性高脂肪饮食后，对饱腹感相关刺激的传入敏感性显著降低。这种变化的主要机制是神经元细胞膜的兴奋性降低。这可以解释当食用高脂肪饮食时发生食欲过盛的原因。提高胃肠道传入神经的敏感性可能有助于限制肥胖症患者的食物摄入。
Non-technical summaryObesity is known to result from energy intake in excess of expenditure. What is not known is how individuals are able to eat in excess of their energy needs. We show that after chronic consumption of a high fat diet (which causes obesity), intestinal sensory nerves are less responsive to chemicals released from the gut during a meal (cholecystokinin and 5-hydroxytryptamine) as well as to distension of the gut as might occur during a meal. This appears to be due to the fact that the ability of the nerve cells to be excited is impaired. This suggests that consumption of an unhealthy diet that leads to obesity causes decreased signalling from the intestine, which may lead to increased food intake and contribute to further weight gain, or allow the maintenance of excess weight and obesity.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 mu m), 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.