Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding
Alice Adriaenssens, … , Fiona Gribble, Frank Reimann
Alice Adriaenssens, … , Fiona Gribble, Frank Reimann
Published May 22, 2023
Citation Information: JCI Insight. 2023;8(10):e164921. https://doi.org/10.1172/jci.insight.164921.
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Research Article Metabolism Neuroscience

Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding

Abstract

Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signaling is critical in GIP-based therapeutics’ ability to lower body weight, but pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC) — brain regions critical to the control of energy balance. Hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP-1R coagonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (GIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to distal brain regions and were transcriptomically distinct. Peripherally dosed fluorescent GIPRAs revealed that access was restricted to circumventricular organs in the CNS. These data demonstrate that Gipr neurons in the hypothalamus, AP, and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility, and appetite-controlling mechanisms. These results highlight the heterogeneity of the central GIPR signaling axis and suggest that studies into the effects of GIP pharmacology on feeding behavior should consider the interplay of multiple regulatory pathways.

Authors

Alice Adriaenssens, Johannes Broichhagen, Anne de Bray, Julia Ast, Annie Hasib, Ben Jones, Alejandra Tomas, Natalie Figueredo Burgos, Orla Woodward, Jo Lewis, Elisabeth O’Flaherty, Kimberley El, Canqi Cui, Norio Harada, Nobuya Inagaki, Jonathan Campbell, Daniel Brierley, David J. Hodson, Ricardo Samms, Fiona Gribble, Frank Reimann

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Figure 2

Gipr expression in the DVC and vagal afferents.

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Gipr expression in the DVC and vagal afferents. (A) Coronal sections fr...
(A) Coronal sections from GiprGCaMP3 mice were stained for GFP (green). Nuclei were counterstained with DAPI (blue). Photomicrograph is representative of experiments conducted in tissue from 5 separate mice. Original magnification: ×20 (A and B). (B) Coronal sections of mouse brain stem tissue from C57BL/6 mice were probed for Gipr expression using FISH (green). Nuclei are counterstained with DAPI (blue). Photomicrograph is representative of experiments conducted in tissue from 3 separate mice. (C) qPCR was performed in pooled samples of nodose ganglia (n = 5–6 mice per replicate) for Gipr and Glp1r expression. Expression levels were calculated relative to Actb. Data presented as 2ΔCT ± SEM. (D) Sections of nodose ganglia isolated from C57BL/6 mice were probed for Gipr (magenta), Oxtr (yellow), and Glp1r (cyan) expression using FISH. Neurons were stained for HuC/D (gray). Photomicrograph is representative of experiments conducted in tissue from 4 separate mice. Scale bars: 100 μm and 10 μm (insets). Arrows indicate Gipr postitive cells.