JCI Insight. 2019 Sep 5;4(17):130402. doi: 10.1172/jci.insight.130402.
Research shows that rats and humans on a high-fat diet (HFD) are less sensitive to satiety signals known to act via vagal afferent pathways. We hypothesize that HFD causes an upregulation of 2-pore domain potassium channels, resulting in hyperpolarization of nodose ganglia (NG) and decreased vagal response to satiety signals, which contribute to hyperphagia. We show that a 2-week HFD caused an upregulation of 2-pore domain TWIK-related spinal cord K+ (TRESK) and TWIK-related acid-sensitive K+ 1 (TASK1) channels by 330% ± 50% and 60% ± 20%, respectively, in NG. Patch-clamp studies of isolated NG neurons demonstrated a decrease in excitability. In vivo single-unit NG recordings showed that a 2-week HFD led to a 55% reduction in firing frequency in response to CCK-8 or leptin stimulation. NG electroporation with TRESK siRNA restored NG responsiveness to CCK-8 and leptin. Rats fed a 2-week HFD consumed ~40% more calories compared with controls. Silencing NG TRESK but not TASK1 channel expression in HFD-fed rats restored normal calorie consumption. In conclusion, HFD caused upregulation of TRESK channels, resulting in NG hyperpolarization and decreased vagal responsiveness to satiety signals. This finding provides a pharmacological target to prevent or treat HFD-induced hyperphagia.
研究表明，高脂肪饮食（HFD）的大鼠和人类对已知通过迷走传入途径起作用的饱腹感信号的敏感性降低。我们假设 HFD 导致 2 孔域钾通道上调，导致迷走神经节（NG）超极化和饱腹感信号对迷走神经反应降低，这导致过度进食。我们表明，2 周 HFD 导致 NG 中 2 孔 TWIK 相关脊髓 K +（TRESK）和 TWIK 相关酸敏感 K +1（TASK1）通道分别上调 330%±50%和 60%±20%。分离的 NG 神经元的膜片钳研究表明兴奋性降低。体内单单位 NG 记录表明，2 周 HFD 导致对 CCK-8 或瘦素刺激的放电频率降低 55%。NG 电穿孔用 TRESK siRNA 恢复了 NG 对 CCK-8 和瘦素的反应性。与对照组相比，2 周 HFD 喂养的大鼠消耗的卡路里约增加了 40%。沉默 HFD 喂养大鼠的 NG TRESK 但不沉默 TASK1 通道表达可恢复正常卡路里消耗。总之，HFD 导致 TRESK 通道上调，导致 NG 超极化和饱腹感信号对迷走神经反应降低。这一发现为预防或治疗 HFD 诱导的过度进食提供了药理学靶点。
