High-fat diet–induced vagal afferent dysfunction via upregulation of 2-pore domain potassium TRESK channel
Authors: Chung Owyang
Gintautas Grabauskas
Xiaoyin Wu
Jun Gao
ShiYi Zhou
JiYao Li
Journal: JCI Insight (2019)
Discipline: CLINICAL MEDICINE
Keywords: Endocrinology; Gastroenterology; Homeostasis; Ion channels; Obesity.

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. 

Retracted: No

PubPeer comments:
 A MAJOR issue with Figure 2. Double immunohistochemistry using two rabbit antibodies is not valid. The listed primary antibodies are all polyclinal rabbit: The anti-Tresk is a rabbit polyclonal: https: www.alomone.com p anti-k2p18-1-tresk-extracellular APC-122 The anti-CCKAR sc-270029 couldn t be found. Perhaps, they used the same antibody as in a prior study, a rabbit polyclonal: https: www.scbt.com scbt product cck-ar-antibody-h-60 The listed anti-LepR is a rabbit polyclonal too: https: datasheets.scbt.com sc-8325.pdf On top of that, a dilution of 1 200 is very concentrated and antibodies against receptors are notoriously unreliable (see PMID: 29355666). If true, the immunostainings are NOT valid. A similar issue was already flagged in another paper: https: pubpeer.com publications 3997DF0EFFD027DBE6094ECCFC4B2B , 
 ![file] , 
 #1  A MAJOR issue with Figure 2 Fig 3.  (A) Representative recordings of NG neuron responses to intrau2013superior pancreaticoduodenal artery infusions of CCK-8 (60 pmol kg) and leptin (60 pmol kg) in LFD-fed or HFD-fed rats and transfected with control siRNA or TRESK siRNA. The CCK-8 and leptin recordings for LFD control-siRNA appear to have identical baselines of noise, and share a surprising number of identically-timed spikes. Dramatised at bottom by black-white reversing the CCK-8 version and superimposing it on the leptin version, so white and black spikes are unique to the former and latter respectively, while shared ones cancel out and create a gray picket-fence effect. In short, they are **too** representative. This may also be a MAJOR problem. ![file] , 
 Figure 3 again. In the HFD TRESK conditions, could the authors comment on the similarity between the end of the CCK-8 recording and the beginning of the Leptin recording? As if the latter is a continuation of the former? ![file] , 
 #4 Hoya, you missed a few things: ![file] , 
 The patch-clamp experiments performed by 1st author are, however, of solid quality , 
 Corriegendum [March 26, 2020] :  During the assembly of Figure 3, the authors inadvertently included incorrect data in panel C. The authors were able to provide the original data, and a corrected version of Figure 3C appears below.  In addition, the Methods section incorrectly indicated the manufacturer and catalog number for the TRESK antibody used for immunocytochemistry. The corrected statement appears below.  Immunocytochemistry studies to localize TRESK (sc-51240, Santa Cruz Biotechnology) and CCK-AR (sc-270029, Cell Signaling Technology) were performed on vagal sensory ganglia as described previously (12).  The online version of the article has been updated with the corrected information.  The authors regret the errors. ![] , 
 That doesn t address the electrophysiology issues? ,