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

被引：36

作者：

Adriaenssens, Alice ^{[1
,2
,3
]}

Broichhagen, Johannes ^{[4
]}

de Bray, Anne ^{[5
,6
,7
]}

Ast, Julia ^{[5
,6
,7
]}

Hasib, Annie ^{[6
,7
]}

Jones, Ben ^{[8
]}

Tomas, Alejandra ^{[8
]}

Burgos, Natalie Figueredo ^{[3
]}

Woodward, Orla ^{[1
,2
]}

Lewis, Jo ^{[1
,2
]}

O'Flaherty, Elisabeth ^{[1
,2
]}

El, Kimberley ^{[9
]}

Cui, Canqi ^{[9
]}

Harada, Norio ^{[10
]}

Inagaki, Nobuya ^{[10
]}

Campbell, Jonathan ^{[9
]}

Brierley, Daniel ^{[3
]}

Hodson, David J. ^{[5
,6
,7
]}

Samms, Ricardo ^{[11
]}

Gribble, Fiona ^{[1
,2
]}

Reimann, Frank ^{[1
,2
]}

机构：

[1] Univ Cambridge, Inst Metab Sci, Cambridge, England

[2] Univ Cambridge, MRC Metab Dis Unit, Cambridge, England

[3] UCL, Dept Neurosci Physiol & Pharmacol, London, England

[4] Leibniz Forschungsinst Mol Pharmakol FMP, Berlin, Germany

[5] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab OCDEM, NIHR Oxford Biomed Res Ctr,Dept Med, Oxford, England

[6] Univ Birmingham, Inst Metab & Syst Res IMSR, Birmingham, England

[7] Univ Birmingham, Ctr Membrane Prot & Receptors COMPARE, Birmingham, England

[8] Imperial Coll London, Dept Metab Digest & Reprod, London, England

[9] Duke Univ Hosp, Dept Med, Durham, NC USA

[10] Kyoto Univ, Dept Diabet Endocrinol & Nutr, Kyoto, Japan

[11] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN USA

来源：

JCI INSIGHT | 2023年 / 8卷 / 10期

基金：

英国惠康基金; 欧洲研究理事会;

关键词：

ARCUATE NUCLEUS; INDUCED NAUSEA; FOOD-INTAKE; GLP-1; GIP; AGONIST; WEIGHT; EXPRESSION; CIRCUIT; OBESITY;

D O I：

10.1172/jci.insight.164921

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：16

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