Neural mechanism underlying the anti-nausea effect of GIP
Minrong Ai1*, Brandy Snider1, Alessia Costa2, Richard Cosgrove1, Ricardo Samms1, Paul Emmerson1, Giuseppe D’Agostino2,3, Simon M Luckman2
1Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana, United States
2Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
3The Rowett Institute, University of Aberdeen, Aberdeen, UK
The success of the dual-incretin receptor agonist, Tirzepatide, in the clinic raises great interest in understanding the mechanism of action of this molecule. It is well established that GLP-1 acts on the CNS to reduce food intake and body weight, and induces nausea, while relatively little is known about GIP’s action on the brain. We have published evidence from preclinical models including rats and musk shrews which suggests that GIP has an anti-nausea effect1. Using mouse model we now show that GIP suppresses nausea-like aversive behaviors induced by either GLP-1 or PYY, two agents known to cause nausea and vomiting. To understand a possible mechanism underlying this phenomenon, we identified GIP receptor (GIPR) expressing neurons in the area postrema (AP) of rodent and non-human primate brains. These GIPR+ cells are GABAergic inhibitory neurons. Administration (SC) of GIP specifically activated these GIPR-expressing neurons in mouse brain, while GLP-1 administration (SC) activated a separate population of neurons expressing GLP1R within AP. Importantly, activation of the GABAergic GIPR+ neurons in AP suppressed the activity of the neighboring GLP1R+ neurons, suggesting a local inhibitory network. By contrast, GIPR and PYY receptor, Y2R, are expressed in the same neuronal population in AP. Activation of Y2R, a Gi coupled receptor, by peripheral PYY administration decreased cFos induction in these neurons by peripheral GIP treatment. Furthermore, we discovered that GIP and PYY co-administration led to a decreased neural activity in the dorsal parabrachial nucleus, a brain region downstream of AP that mediates aversive behaviors, when compared to PYY administration alone. Together, our results demonstrated an anti-nausea effect of GIP and elucidated a potential underlying neural basis.
1. Borner T. et al., Diabetes 2021 Nov; 70(11): 2545-2553.