Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding
File(s)
Author(s)
Type
Journal Article
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.
Date Issued
2023-05-22
Date Acceptance
2023-04-18
Citation
JCI Insight, 2023, 8 (10)
ISSN
2379-3708
Publisher
American Society for Clinical investigation
Journal / Book Title
JCI Insight
Volume
8
Issue
10
Copyright Statement
© 2023, Adriaenssens
et al. This is an open access article
published under the terms of the
Creative Commons Attribution 4.0
International License.
et al. This is an open access article
published under the terms of the
Creative Commons Attribution 4.0
International License.
License URL
Identifier
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000997596200001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
Subjects
AGONIST
ARCUATE NUCLEUS
CIRCUIT
EXPRESSION
FOOD-INTAKE
GIP
GLP-1
INDUCED NAUSEA
Life Sciences & Biomedicine
Medicine, Research & Experimental
OBESITY
Research & Experimental Medicine
Science & Technology
WEIGHT
Publication Status
Published
Article Number
e164921
Date Publish Online
2023-05-22