Targeting nutrient-induced satiating vagal afferent neurons via TRAP2 mice

The gut-brain neuronal axis is critical for control of food intake, as intestinal nutrients activate vagal afferent neurons to control meal size via release of gut peptides from enteroendocrine cells. However, the specific population of vagal neurons responsible for control of food intake, and the specific signaling pathways which mediate this response following nutrient ingestion is still not fully understood. We utilized TRAP2 (Fos2A-iCreER) mice, which express a tamoxifen-inducible Cre recombinase downstream from the Fos promoter to target specific neuronal populations in the vagus. TRAP2 mice received a bilateral nodose injection of an excitatory DREADD (pAAV-hSyn-DIO-hM4D(Gq)-mCherry), and one week later were implanted with a small intestinal catheter. Following recovery, mice were overnight fasted and given an i.p. injection of 4-hydroxytamoxifen (4-OHT) immediately prior to small intestinal infusion of either saline (SalineTRAP) or intralipid (LipidTRAP), ultimately resulting in Gq DREADD expression selectively in the vagal afferents neurons that were activated following the infusion. For CCK experiments, CCK (CCKTRAP) or PBS (PBSTRAP) i.p. injection was given 30 min following 4-OHT administration, selectively targeting the DREADD to CCK-activated vagal afferent neurons. Utilizing these mice, we demonstrated that injection of DREADD agonist clozapine N-oxide (CNO) following a 12hr fast significantly decreased food intake in LipidTRAP compared to SalineTRAP mice. Furthermore, CCKTRAP mice exhibited a similar reduction in food intake in response to CNO, compared to PBSTRAP animals. These data demonstrate the ability to selectively target nutrient-induced satiating vagal neurons in vivo and reveal that excitation of lipid-activated or CCK-activated vagal afferent neurons is sufficient to decrease food intake. Future studies will be aimed at better understanding these specific neuronal populations. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.