@article{10.1172/jci.insight.130402, author = {Gintautas Grabauskas AND Xiaoyin Wu AND ShiYi Zhou AND JiYao Li AND Jun Gao AND Chung Owyang}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {High-fat diet–induced vagal afferent dysfunction via upregulation of 2-pore domain potassium TRESK channel}, year = {2020}, month = {3}, volume = {4}, url = {https://insight.jci.org/articles/view/130402}, abstract = {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.}, number = {17}, doi = {10.1172/jci.insight.130402}, url = {https://doi.org/10.1172/jci.insight.130402}, }