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other·preclinical research, biomedical research, endocrinology, neurology, nutrition·PMC10322681

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

JCI Insight · 21 authors, 9 centres

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TL;DR

This preclinical mouse study used genetic and chemogenetic tools to show that GIP receptor neurons in the hypothalamus and hindbrain reduce food intake through distinct neural mechanisms, with hindbrain activation also inducing malaise-like behavior.

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The study employed genetic knockdown (hypothalamic Gipr-KO mice) and chemogenetic activation (Gq-DREADD) to investigate the roles of Gipr-expressing neurons in the hypothalamus and dorsal vagal complex (DVC) on feeding and energy balance. The work provides evidence for differential central mechanisms of GIP signaling in feeding control.

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other

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preclinical research

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ORIGINAL PAPER

PMC10322681

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

JCI Insight

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ABSTRACT

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. Keywords: Metabolism, Neuroscience Keywords: Diabetes, Neuroendocrine regulation, Obesity

CITATION EXPORT

Alice Adriaenssens, Johannes Broichhagen, Anne de Bray et al.. Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding. JCI Insight. (2023). https://doi.org/10.1172/jci.insight.164921

AUTHORS

21 · 9 CENTRES

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

1Institute of Metabolic Science & MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom.
2Department of Neuroscience, Physiology, and Pharmacology, University College London, London, United Kingdom.
3Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.
4Oxford Center for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Center, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
5Institute of Metabolism and Systems Research (IMSR) and Center of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, United Kingdom.
6Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.
7Department of Medicine, Duke University Hospital, Durham, North Carolina, USA.
8Department of Diabetes, Endocrinology and Nutrition, Kyoto University, Kyoto, Japan.
9Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.