Mauricio Walker
Pronouns: He/him
Research Mentor(s): Nadejda Bozadjieva Kramer
Research Mentor School/College/Department: Surgery / Medicine
Program:
Authors: Mauricio Walker, Jordan Wean
Session: Session 2 10:00- 10:50 a.m. Hussey Room
Poster:
Abstract
GLP-1R agonists have an increased effect on hunger reduction when paired with GIPR agonists. GIPR agonists alleviate the illness and nausea associated with GLP-1R agonists as well as enhance their anorexic activity but the synergic relationship they show when paired is still unclear. In an attempt to understand the nature of this relationship, this study is attempting to narrow down the subset of neurons within the brain responsible for the increased efficacy of the combination of GLP-1 and GIP agonists. Tirzepatide, the only dual incretin agonist approved for human use, was used to investigate this relationship. Though tirzepatide acts at both the GLP-1 and GIP receptors in humans, its activity at the mouse GIP receptor is low, and thus, for this study, it was treated as a GLP-1 receptor agonist. To make up for this fact, a GIP receptor agonist called D-Ala2-GIP was used in combination with tirzepatide to simulate what might be seen in humans, allowing us to compare the effects of a GLP-1R agonist working alone versus a dual incretin agonist. Three mice strains were used as models: a global GIPR knockout, a GABAergic neuron GIPR knockout, and a glutamatergic GIPR knockout. Mice were first given a conditioned taste aversion test where they were administered either saline, tirzepatide, or tirzepatide and a GIPR agonist paired with saccharine, a sweet compound in their drinking water. Their subsequent preference for either saccharine water or regular water reflected whether the injections caused nausea or aversion. In wild-type mice, we expected to see lower signs of illness in those who are administered Tirzepatide and a GIPR agonist, when compared to mice who were only administered Tirzepatide. Early results suggest that GABAergic neurons are responsible for the anti-aversive effects of GIP receptor agonism, but experiments are ongoing. Then each cohort of mice was given each drug combination daily for 21 days with concurrent body weight and food intake measurements. These experiments revealed that both the global and GABAergic knockouts enhanced the effect of tirzepatide but blocked the extra efficacy conferred by the dual incretin group. Taken together, these data suggest that GABAergic neurons are responsible both for the anti-aversive effects and for the enhanced body weight effects of dual incretin agonism.
