Increased TASK channel-mediated currents underlie high-fat diet induced vagal afferent dysfunction

Area of Science:

• Neuroscience
• Physiology
• Molecular Biology

Background:

• Satiety sensing vagal afferent neurons are less responsive in obesity due to reduced electrical excitability.
• Leak potassium (K+) currents significantly influence neuronal membrane excitability.

Purpose of the Study:

• To investigate the hypothesis that leak K+ currents are increased in vagal afferents during diet-induced obesity.
• To determine the role of TWIK-related acid-sensitive K+ (TASK) channels in obesity-related satiety signaling impairment.

Main Methods:

• Diet-induced obesity model in C57Bl/6J mice using a high-fat diet.
• In vitro extracellular recordings of jejunal afferent nerves and whole-cell patch-clamp recordings of mouse nodose ganglion neurons.
• Isolation of leak K+ currents using ion substitution and pharmacological blockers; mRNA analysis of TASK subunits via quantitative real-time PCR.

Main Results:

• Intestinal afferent responses to nutrient and non-nutrient stimuli were decreased in high-fat diet fed mice.
• Leak K+ current was approximately doubled in neurons from obese mice and was inhibited by TASK1 and TASK3 blockers.
• Quantitative PCR revealed increased TASK3 (KCNK9) transcript levels in high-fat diet fed mice.

Conclusions:

• Increased resting (leak) K+ conductance, mediated by TASK channels, contributes to reduced vagal afferent excitability in diet-induced obesity.
• TASK channels are implicated in the impairment of satiety signaling in obesity, representing a potential therapeutic target.