Figueredo Burgos, N. S.; Lopez-Cruz, A.; Skoug, C.; Roberts, A. G.; Xie, K.; Davies, I.; Harada, N.; Inagaki, N.; Reimann, F.; Gribble, F. M.; Jones, B.; Brierley, D. I.; Trapp, S.; Knight, Z. A.; Adriaenssens, A. E.

Central glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling is required for the efficacy of GIP-based obesity therapeutics, yet how distinct subpopulations of GIPR neurons shape appetite remains undefined. Here we show that GIPR neurons in adjacent brainstem nuclei, the area postrema (AP) and nucleus tractus solitarius (NTS), exert opposing control over ingestion. We find GIPRAP neurons dampen post-ingestive satiation, permitting hyperphagia, whereas GIPRNTS neurons are anorectic. In line with this model, we show Gipr expression in AP, but not NTS, neurons is necessary for appetite suppression following GIPR antagonism. Additionally, we reveal that GIPR neurons in the AP and NTS occupy distinct gut-brain circuits, and are differentially sensitive to obesity-driven circuit remodelling. These data offer a framework for understanding how current GIPR agonist and antagonist strategies elicit weight loss.