Coupling of oxytocin and cholecystokinin pathways in the hypothalamus is required for gut-to-brain homeostatic feeding control
Coupling of oxytocin and cholecystokinin pathways in the hypothalamus is required for gut-to-brain homeostatic feeding control
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 chow diet. Notably, exposing wildtype mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity towards CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in DIO mice via chemogenetics or polypharmacology sufficiently re-establishes CCK’s anorexigenic effects. Lastly, by single-cell profiling, we identify a specialized PVNOT neuronal subpopulation with increased κ-opioid signaling under HFHS diet, which restrains their CCK-evoked activation. In sum, we here document a novel (patho)mechanism by which PVNOT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.
Sanchez-Quant E、Miok V、Gonz¨￠lez-Garc¨aa I、Tsch?p MH、Woods SC、M¨1ller TD、Murat C、Contreras RE、Gruber T、Grinevich V、Le Thuc O、Williams RH、Lechner F、Martinez-Jimenez CP、Pfluger PT、Garc¨aa-C¨￠ceres C
Helmholtz Pioneer Campus (HPC), Helmholtz Zentrum M¨1nchenInstitute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum M¨1nchen, German Research Center for Environmental Health (GmbH)||German Center for Diabetes Research (DZD)Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum M¨1nchen, German Research Center for Environmental Health (GmbH)||German Center for Diabetes Research (DZD)Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum M¨1nchen, German Research Center for Environmental Health (GmbH)||German Center for Diabetes Research (DZD)||Division of Metabolic Diseases, Department of Medicine, Technische Universit?tDepartment of Psychiatry and Behavioral Neuroscience, University of CincinnatiInstitute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum M¨1nchen, German Research Center for Environmental Health (GmbH)||German Center for Diabetes Research (DZD)||Department of Pharmacology and Experimental Therapy, Institute for Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls Hospitals and ClinicsInstitute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum M¨1nchen, German Research Center for Environmental Health (GmbH)||German Center for Diabetes Research (DZD)Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum M¨1nchen, German Research Center for Environmental Health (GmbH)||German Center for Diabetes Research (DZD)Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum M¨1nchen, German Research Center for Environmental Health (GmbH)||German Center for Diabetes Research (DZD)Department of Neuropeptide Research in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg||Center for Neuroinflammation and Cardiometabolic Diseases, Georgia State UniversityInstitute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum M¨1nchen, German Research Center for Environmental Health (GmbH)||German Center for Diabetes Research (DZD)Helmholtz Zentrum M¨1nchen, German Research Center for Environmental Health, Institute for NeurogenomicsInstitute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum M¨1nchen, German Research Center for Environmental Health (GmbH)||German Center for Diabetes Research (DZD)Helmholtz Pioneer Campus (HPC), Helmholtz Zentrum M¨1nchen||TUM School of Medicine, Technical University of MunichInstitute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum M¨1nchen, German Research Center for Environmental Health (GmbH)||German Center for Diabetes Research (DZD)||Research Unit NeuroBiology of Diabetes||Neurobiology of Diabetes, TUM School of Medicine, Technical University MunichInstitute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum M¨1nchen, German Research Center for Environmental Health (GmbH)||German Center for Diabetes Research (DZD)||Medizinische Klinik und Poliklinik IV, Klinikum der Universit?t, Ludwig-Maximilians-Universit?t M¨1nchen
基础医学生理学神经病学、精神病学
obesitygut-brain axisoxytocinparaventricular hypothalamic nucleusCCKopioids
Sanchez-Quant E,Miok V,Gonz¨￠lez-Garc¨aa I,Tsch?p MH,Woods SC,M¨1ller TD,Murat C,Contreras RE,Gruber T,Grinevich V,Le Thuc O,Williams RH,Lechner F,Martinez-Jimenez CP,Pfluger PT,Garc¨aa-C¨￠ceres C.Coupling of oxytocin and cholecystokinin pathways in the hypothalamus is required for gut-to-brain homeostatic feeding control[EB/OL].(2025-03-28)[2025-06-14].https://www.biorxiv.org/content/10.1101/2022.07.20.500778.点此复制
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