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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)

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Oxytocin-expressing paraventricular hypothalamic neurons (PVN^OT neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVN^OT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVN^OT 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 PVN^OT 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 PVN^OT 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 PVN^OT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords 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

Journal Cell Reports

Quellenangaben Volume: 42, Issue: 10, Article Number: 113305

Publisher Cell Press

Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Obesity (IDO)
Helmholtz Pioneer Campus (HPC)
Institute of Neurogenomics (ING)

Grants 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