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GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior

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posted on 02.05.2022, 13:00 authored by Ricardo J Samms, Richard Cosgrove, Brandy M Snider, Ellen C Furber, Brian A Droz, Daniel A Briere, James Dunbar, Mridula Dogra, Jorge Alsina-Fernandez, Tito Borner, Bart C. De Jonghe, Matthew R. Hayes, Tamer Coskun, Kyle W Sloop, Paul J Emmerson, Minrong Ai

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 agonism reduces PYY-induced nausea-like behavior in mice. We found that central and peripheral administration of a GIPR agonist (GIPRA) 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 GIPRA 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 GIPRA treatment reduces PYY-induced nausea-like behavior. Together, our study provides a novel mechanism by which GIP-based therapeutics may benefit the tolerability of weight loss agents. 

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