TY - JOUR AU - Grabauskas, Gintautas AU - Wu, Xiaoyin AU - Zhou, ShiYi AU - Li, JiYao AU - Gao, Jun AU - Owyang, Chung T1 - High-fat diet–induced vagal afferent dysfunction via upregulation of 2-pore domain potassium TRESK channel PY - 2020/03/20/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.130402 VL - 4 IS - 17 UR - https://doi.org/10.1172/jci.insight.130402 PB - The American Society for Clinical Investigation ER -