GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior

• Published in: Diabetes (New York, N.Y.) Vol. 71; no. 7; pp. 1410 - 1423
• Main Authors: Samms, Ricardo J., Cosgrove, Richard, Snider, Brandy M., Furber, Ellen C., Droz, Brian A., Briere, Daniel A., Dunbar, James, Dogra, Mridula, Alsina-Fernandez, Jorge, Borner, Tito, De Jonghe, Bart C., Hayes, Matthew R., Coskun, Tamer, Sloop, Kyle W., Emmerson, Paul J., Ai, Minrong
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.07.2022
• Subjects: Agonists; Area postrema; Body weight loss; Brain stem; Diabetes; Feeding behavior; GIP protein; Hypophagia; Nausea; Obesity; Obesity Studies; Parabrachial nucleus; Rodents; Side effects; Vomiting; Weight control
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db21-0848

The induction of nausea and emesis is a major barrier to maximizing the weight loss profile of obesity medications, and therefore, identifying mechanisms that improve tolerability could result in added therapeutic benefit. The development of peptide YY (PYY)-based approaches to treat obesity are no exception, as PYY receptor agonism is often accompanied by nausea and vomiting. Here, we sought to determine whether glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) agonism reduces PYY-induced nausea-like behavior in mice. We found that central and peripheral administration of a GIPR agonist reduced conditioned taste avoidance (CTA) without affecting hypophagia mediated by a PYY analog. The receptors for GIP and PYY (Gipr and Npy2r) were found to be expressed by the same neurons in the area postrema (AP), a brainstem nucleus involved in detecting aversive stimuli. Peripheral administration of a GIPR agonist induced neuronal activation (cFos) in the AP. Further, whole-brain cFos analyses indicated that PYY-induced CTA was associated with augmented neuronal activity in the parabrachial nucleus (PBN), a brainstem nucleus that relays aversive/emetic signals to brain regions that control feeding behavior. Importantly, GIPR agonism reduced PYY-mediated neuronal activity in the PBN, providing a potential mechanistic explanation for how GIPR agonist treatment reduces PYY-induced nausea-like behavior. Together, the results of our study indicate a novel mechanism by which GIP-based therapeutics may have benefit in improving the tolerability of weight loss agents.