The generation of nausea and emesis is a significant obstacle to optimizing the weight loss profile of obesity drugs; hence, discovering strategies that increase tolerability might result in further therapeutic benefits. Peptide YY receptor agonism is frequently accompanied by nausea and vomiting. Therefore the development of PYY-based therapies to treat obesity is no exception. Researchers sought to determine if glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) agonism lowers PYY-induced nausea-like behavior for a study. 

They discovered that central and peripheral injection of a GIPR agonist decreased conditioned taste avoidance (CTA) while not affecting hypophagia caused by a PYY analog. GIP and PYY receptors (Gipr and Npy2r) were discovered to be expressed by the same neurons in the area postrema (AP), a brainstem nucleus involved in detecting unpleasant stimuli. A GIPR agonist administered peripherally promoted neuronal activity (cFos) in the AP. PYY-induced CTA was also related to increased neuronal activity in the parabrachial nucleus (PBN). The brainstem nucleus conveys aversive/emetic signals to brain areas that influence eating behavior, according to whole-brain cFos studies. 

GIPR agonism decreased PYY-mediated neuronal activity in the PBN, suggesting a possible molecular explanation for how GIPR agonist therapy lowers PYY-induced nausea-like behavior. The findings suggested a potential method for GIP-based treatments to increase the tolerance of weight loss medications.