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Gruber, T. ; Contreras, R. ; Sánchez Quant, E.S. ; Miok, V. ; Makris, K. ; Le Thuc, O. ; Gonzales García, I. ; Garcia-Clavé, E. ; Althammer, F.* ; Krabichler, Q.* ; DeCamp, L.M.* ; Jones, R.G.* ; Lutter, D. ; Williams, R.H. ; Pfluger, P.T. ; Müller, T.D. ; Woods, S.C.* ; Pospisilik, J.A.* ; Martinez-Jimenez, C.P.* ; Tschöp, M.H. ; Grinevich, V.* ; García-Cáceres, C.

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

Cell Rep. 42:113305 (2023)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cck ; Cp: Neuroscience ; Nts ; Pvn ; Gut Hormone ; Gut-brain Axis ; Neuropeptide ; Obesity ; Opioids ; Oxytocin ; Paraventricular Hypothalamic Nucleus; High-fat Diet; Paraventricular Nucleus; Food-intake; Noradrenaline Release; Rna-seq; Supraoptic Nucleus; Vagal Afferent; Messenger-rna; Cholecystokinin; Receptor
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Zeitschrift Cell Reports
Quellenangaben Band: 42, Heft: 10, Seiten: , Artikelnummer: 113305 Supplement: ,
Verlag Cell Press
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
Helmholtz Pioneer Campus (HPC)
Institute of Neurogenomics (ING)
Förderungen European Union
European 748 Research Council ERC
Helmholtz Pioneer Campus
German Research Foundation (DFG)
Marie Sk1odowska-Curie grant
German Center for Diabetes Research (DZD e.V.)
European Research Council ERC-CoG Trust
Germany-Israel Excellence Program
European Research Council (ERC) (Synergy ERC)
European Research Council (ERC)
Helm-holtz Excellence Network
German Center for Diabetes Research (DZD) twinning grant