GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior.

Autor:	Samms RJ; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN., Cosgrove R; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN., Snider BM; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN., Furber EC; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN., Droz BA; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN., Briere DA; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN., Dunbar J; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN., Dogra M; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN., Alsina-Fernandez J; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN., Borner T; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA., De Jonghe BC; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA., Hayes MR; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA., Coskun T; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN., Sloop KW; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN., Emmerson PJ; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN., Ai M; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2022 Jul 01; Vol. 71 (7), pp. 1410-1423.
DOI:	10.2337/db21-0848
Abstrakt:	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. (© 2022 by the American Diabetes Association.)
Databáze:	MEDLINE
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