| First Author | Gruber T | Year | 2023 |
| Journal | Cell Rep | Volume | 42 |
| Issue | 10 | Pages | 113305 |
| PubMed ID | 37864798 | Mgi Jnum | J:342329 |
| Mgi Id | MGI:7548213 | Doi | 10.1016/j.celrep.2023.113305 |
| Citation | Gruber T, et al. (2023) High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via kappa-opioid signaling. Cell Rep 42(10):113305 |
| abstractText | Oxytocin-expressing paraventricular hypothalamic neurons (PVN(OT) neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVN(OT) neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVN(OT) neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVN(OT) neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK's anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVN(OT) neuronal subpopulation with increased kappa-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVN(OT) signaling uncouples a gut-brain satiation pathway under obesogenic conditions. |
