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High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling

Oxytocin-expressing paraventricular hypothalamic neurons (PVNOT neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVNOT neurons orchestrate gut-to-brain feeding control remain uncl...

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Main Authors: Gruber, Tim (Author) , Lechner, Franziska (Author) , Murat, Cahuê (Author) , Contreras, Raian E. (Author) , Sanchez-Quant, Eva (Author) , Miok, Viktorian (Author) , Makris, Konstantinos (Author) , Le Thuc, Ophélia (Author) , González-García, Ismael (Author) , García-Clave, Elena (Author) , Althammer, Ferdinand (Author) , Krabichler, Quirin (Author) , DeCamp, Lisa M. (Author) , Jones, Russell G. (Author) , Lutter, Dominik (Author) , Williams, Rhiannan H. (Author) , Pfluger, Paul T. (Author) , Müller, Timo D. (Author) , Woods, Stephen C. (Author) , Pospisilik, John Andrew (Author) , Martinez-Jimenez, Celia P. (Author) , Tschöp, Matthias H. (Author) , Grinevich, Valéry (Author) , García-Cáceres, Cristina (Author)
Format: Article (Journal)
Language:English
Published: 31 October 2023
In: Cell reports
Year: 2023, Volume: 42, Issue: 10, Pages: 1-26
ISSN:2211-1247
DOI:10.1016/j.celrep.2023.113305
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.celrep.2023.113305
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S2211124723013177
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Author Notes:Tim Gruber, Franziska Lechner, Cahuê Murat, Raian E. Contreras, Eva Sanchez-Quant, Viktorian Miok, Konstantinos Makris, Ophélia Le Thuc, Ismael González-García, Elena García-Clave, Ferdinand Althammer, Quirin Krabichler, Lisa M. DeCamp, Russell G. Jones, Dominik Lutter, Rhiannan H. Williams, Paul T. Pfluger, Timo D. Müller, Stephen C. Woods, John Andrew Pospisilik, Celia P. Martinez-Jimenez, Matthias H. Tschöp, Valery Grinevich, and Cristina García-Cáceres
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Summary:Oxytocin-expressing paraventricular hypothalamic neurons (PVNOT neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVNOT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVNOT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK’s anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVNOT neuronal subpopulation with increased κ-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVNOT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.
Item Description:Online verfügbar 31 October 2023, Version des Artikels 31 October 2023
Gesehen am 29.01.2024
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2023.113305

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