Background: Circadian synchrony between the time of activity and food intake is critical for maintaining chrono-metabolic homeostasis. Rodent and human studies have shown that desynchrony between food intake and activity is detrimental to organismal health as shift working individuals are at an increased risk for developing metabolic diseases (e.g., obesity). Feeding behaviors are primarily regulated by hypothalamic and hindbrain sites that integrate metabolic information from peripheral organs. However, it is unclear how this information is sent from peripheral organs to the brain to ensure synchrony in feeding and activity. The parasympathetic vagus nerve is a mixed motor/sensory nerve with sensory afferents that relay the metabolic status of peripheral organs by first synapsing in the nodose ganglia and then in the dorsal vagal complex (DVC) before projecting to metabolic regulatory areas throughout the brain. The vagus nerve is an established mode of communication between the brain and periphery that can indicate the timing of food intake by circadian variation in signal sensitivity. Therefore, we hypothesize that the subdiaphragmatic vagus nerve (SD) relays signals from the periphery to metabolic and energy balance centers in the brain indicating eating at the “wrong” time of day. Methods: We used a cFos reporter mouse line (TRAP2 x Ai14) to conditionally express tdTomato in neurons activated by food intake. We fed mice for one hour either during the light phase (mistimed eating) or dark phase (timed eating) before injecting 4-hydroxytamoxifen (4OHT) to induce Cre-dependent recombination in neurons activated by timed food intake. To determine whether these mistimed eating-sensitive (MES) neurons received signals from the gastrointestinal tract through the vagus nerve we surgically resected the SD (SDx) in TRAP2 x Ai14 mice before one hour of mistimed eating followed by 4OHT injection. Results: We discovered distinct subpopulations of neurons in the hypothalamus and hindbrain that are uniquely activated by mistimed eating. We also observed SDx increased the number of MES neurons in the hypothalamus and hindbrain compared to Sham operated animals. Conclusions: Our results reveal a unique neurobiological response to mistimed eating and indicate that the vagus nerve regulates the intensity of this response. As mistimed eating is detrimental to metabolic health, it is essential to identify interventions to protect individuals who are eating at the wrong time of day (e.g., shift workers). Our work suggests the vagus nerve as a target for such therapies to alleviate the burden of mistimed eating on human health. 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.
Woodie et al. (Fri,) studied this question.