RYGB induces vagal sensory neuropathy characterized by altered Glp1r expression and enhanced exendin-4 responsiveness in male mice.

The effects of Roux-en-Y gastric bypass (RYGB) on the gut-brain axis remain poorly understood. This study specifically explores phenotypic changes in vagal afferent neurons in male obese C57BL/6J mice following RYGB. Our results show that RYGB induced the expression of activating transcription factor 3 () mRNA-a well-established marker of axonal injury-in a subset of vagal sensory neurons. In addition, RYGB led to a significant reduction in both the proportion of vagal afferents expressing the glucagon-like peptide 1 receptor (GLP1R) and the overall mRNA levels in the nodose ganglion. Nerve transection experiments replicated these changes, suggesting that axonal injury alone may account for the observed phenotypic alterations in vagal afferent neurons following RYGB. Electrophysiological recordings further revealed that acute administration of exendin-4, a GLP1R agonist, significantly enhanced afferent vagus nerve firing. Interestingly, this response was notably exaggerated in RYGB animals and those with injured gastric vagus nerves. Collectively, these findings provide both molecular and electrophysiological evidence that RYGB induces vagal neuropathy, characterized by reduced Glp1r expression and heightened sensitivity to GLP1. Roux-en-Y gastric bypass in obese mice triggered markers of vagal nerve injury, reduced Glp1r-expressing vagal afferents, and lowered mRNA in the nodose ganglion. Nerve injury experiments reproduced these effects. Despite reduced receptor expression, GLP1R agonist-evoked vagal firing was exaggerated after RYGB or vagal injury. Overall, the findings indicate RYGB causes vagal neuropathy with diminished expression but heightened GLP1 sensitivity.