GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior

Abstract

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 induced by a PYY analog. The receptors for GIP and PYY (Gipr and Npy2r) were expressed by the same neurons in the area postrema (AP), a brainstem nucleus involved in the detection of 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), an area of the brain that relays aversive/emetic stimuli 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.

Design of Xenopus GLP-1-Based Long-Acting Dual GLP-1/Y2 Receptor Agonists

“…%Baseline food intake was calculated using the following equation: 100% rodent chow consumption in the tested peptide group)/rodent chow consumption in the saline group] × 100%. For conditioned taste aversion (CTA) assay, 47 male C57BL/6J mice (10−12 weeks) were divided into seven groups and individually housed and allowed free access to water and food. In each cage, two water bottles were placed with equal access to food on both sides.…”

“…For conditioned taste aversion (CTA) assay, male C57BL/6J mice (10–12 weeks) were divided into seven groups and individually housed and allowed free access to water and food. In each cage, two water bottles were placed with equal access to food on both sides.…”

Sensory innervation of masseter, temporal and lateral pterygoid muscles in common marmosets

“…Finally, tissue sections were washed for 3 × 5 minutes with 0.1M PBS and 2 × 5 minutes in diH 2 O, air-dried, and covered with Vectashield Antifade Mounting Medium (Vectorlabs, Burlingame, CA, USA). In this study, the following previously characterized primary antibodies were used: anti-PGP9.5 rabbit polyclonal (Millipore-Sigma; Burlington, NJ, catalog AB1761-I; 1:300) (Boyd et al, 2021); anti-Neurofilament H (NF-H) chicken polyclonal (BioLegend; San Diego, CA; catalog 822601; 1:1000) (Avona et al, 2021); anti-CGRP guinea pig polyclonal (Synaptic Systems; Goettingen, Germany; catalog 414 004; 1:200) (Samms et al, 2022); anti-TRPV1 rabbit polyclonal (Novus Biologicals; Centennial, CO; catalog NBP1-71774SS; 1:200) (Moutafidi et al, 2021); anti-mrgprD rabbit polyclonal (Alamone Lab; catalog ASR-031; 1:200) (de Carvalho Santuchi et al, 2019; Lindquist et al, 2021); anti-CHRNA3 rabbit polyclonal (Bioss; catalog BS-6455R; 1:200) (He et al, 2014); anti-tyrosine hydroxylase (TH) chicken polyclonal (Neuromics; Bloomington, MN; catalog CH23006; 1:300) (Ferreira-Pinto et al, 2021); anti-smooth muscle actin (α-SMA) Cy3-conjugated rabbit polyclonal antibody (Millipore-Sigma; catalog C6198; 1:500); anti-trkC rabbit polyclonal (Aviva Systems Biology, San Diego, CA; catalog ARP51318_P050; 1:200); anti-trkB goat polyclonal (R&D systems; AF1494; 1:200) (Arcourt et al, 2017); anti-parvalbumin rabbit polyclonal (Novus Biologicals; catalogue NB120-11427SS; 1:200) (Lewis et al, 2021); anti-calbindin D28k rabbit polyclonal (Synaptic Systems; catalogue 214 011; 1:200) (Navarro-Gonzalez et al, 2021).…”

“…Finally, tissue sections were washed for 3 x 5 minutes with 0.1M PBS and 2 x 5 minutes in diH2O, air-dried, and covered with Vectashield Antifade Mounting Medium (Vectorlabs, Burlingame, CA, USA). In this study, the following previously characterized primary antibodies were used: anti-PGP9.5 rabbit polyclonal (Millipore-Sigma; Burlington, NJ, catalog AB1761-I; 1:300) (Boyd et al, 2021); anti-Neurofilament H (NF-H) chicken polyclonal (BioLegend; San Diego, CA; catalog 822601; 1:1000) (Avona et al, 2021); anti-CGRP guinea pig polyclonal (Synaptic Systems; Goettingen, Germany; catalog 414 004; 1:200) (Samms et al, 2022); anti-TRPV1 rabbit polyclonal (Novus Biologicals; Centennial, CO; catalog NBP1-71774SS; 1:200) (Moutafidi et al, 2021); anti-mrgprD rabbit polyclonal (Alamone Lab;…”

Dual gut hormone receptor agonists for diabetes and obesity

“…First, through biased agonism at the GLP1R, tirzepatide induces faster recycling of internalized GLP1R compared with GLP1R monoagonism ( 23 ). Second, evidence suggests a global antiaversive effect of GIPR agonism, which could allow for enhanced GLP1R agonism while minimizing nausea and other gastrointestinal side effects that limit GLP1R agonist tolerability ( 24 , 25 ). The GIPRs studied in antiaversion studies are located in the brain stem, separate from the hypothalamic receptors that may mediate the direct effect of GIPR agonism on food intake.…”