JCI Insight. 2021 May 10;6(9):139785. doi: 10.1172/jci.insight.139785.
Acute high-fat diet (aHFD) exposure induces a brief period of hyperphagia before caloric balance is restored. Previous studies have demonstrated that this period of regulation is associated with activation of synaptic N-methyl-D-aspartate (NMDA) receptors on dorsal motor nucleus of the vagus (DMV) neurons, which increases vagal control of gastric functions. Our aim was to test the hypothesis that activation of DMV synaptic NMDA receptors occurs subsequent to activation of extrasynaptic NMDA receptors. Sprague-Dawley rats were fed a control or high-fat diet for 3-5 days prior to experimentation. Whole-cell patch-clamp recordings from gastric-projecting DMV neurons; in vivo recordings of gastric motility, tone, compliance, and emptying; and food intake studies were used to assess the effects of NMDA receptor antagonism on caloric regulation. After aHFD exposure, inhibition of extrasynaptic NMDA receptors prevented the synaptic NMDA receptor-mediated increase in glutamatergic transmission to DMV neurons, as well as the increase in gastric tone and motility, while chronic extrasynaptic NMDA receptor inhibition attenuated the regulation of caloric intake. After aHFD exposure, the regulation of food intake involved synaptic NMDA receptor-mediated currents, which occurred in response to extrasynaptic NMDA receptor activation. Understanding these events may provide a mechanistic basis for hyperphagia and may identify novel therapeutic targets for the treatment of obesity.
急性高脂肪饮食（aHFD）暴露会在恢复热量平衡之前引起短暂的过度进食期。先前的研究表明，这种调节期与迷走神经背核（DMV）神经元上突触 N-甲基-D-天冬氨酸（NMDA）受体的激活有关，这增加了迷走神经对胃功能的控制。我们的目的是测试这样一个假设，即 DMV 突触 NMDA 受体的激活发生在 extrasynaptic NMDA 受体的激活之后。在实验前，SD 大鼠连续 3-5 天接受对照或高脂肪饮食喂养。使用全细胞膜片钳记录胃投射 DMV 神经元；胃动力、张力、顺应性和排空的体内记录；以及食物摄入量研究，以评估 NMDA 受体拮抗剂对热量调节的影响。在 aHFD 暴露后，抑制 extrasynaptic NMDA 受体可防止 DMV 神经元中谷氨酸能传递的突触 NMDA 受体介导的增加，以及胃张力和动力的增加，而慢性 extrasynaptic NMDA 受体抑制可减弱对热量摄入的调节。在 aHFD 暴露后，进食调节涉及突触 NMDA 受体介导的电流，这是 extrasynaptic NMDA 受体激活的反应。了解这些事件可能为过度进食提供机制基础，并为肥胖症的治疗确定新的治疗靶点。
