Coupling of oxytocin and cholecystokinin pathways in the hypothalamus is required for gut-to-brain homeostatic feeding control

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. ### Competing Interest Statement The authors declare no competing interests. Dr. Matthias Tschoep is a member of the scientific advisory board of ERX Pharmaceuticals, Inc., Cambridge, MA. He is on the scientific advisory board of The LOOP Zurich Medical Research Center and the advisory board of the BIOTOPIA Naturkundemuseum Bayern. He is also a member of the board of trustees of the Max Planck Institutes of Neurobiology and Biochemistry, Martinsried, and the scientific advisory board of the Max Planck Institute for Metabolism Research, Cologne. He was a member of the Research Cluster Advisory Panel (ReCAP) of the Novo Nordisk Foundation between 2017-2019. He attended a scientific advisory board meeting of the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, in 2016. He received funding for his research projects by Novo Nordisk (2016-2020) and Sanofi-Aventis (2012-2019). He was a consultant for Bionorica SE (2013-2017), Menarini Ricerche S.p.A. (2016), Bayer Pharma AG Berlin (2016) and Boehringer Ingelheim Pharma GmbH & Co. KG (2020/2021). He delivered a scientific lecture for Sanofi-Aventis Deutschland GmbH in 2020. As former Director of the Helmholtz Diabetes Center and the Institute for Diabetes and Obesity at Helmholtz Zentrum Muenchen (2011-2018) and since 2018, as CEO of Helmholtz Munich, he has been responsible for collaborations with a multitude of companies and institutions, worldwide. In this capacity, he discussed potential projects with and has signed/signs contracts for his institute(s) and for the staff for research funding and/or collaborations with industry and academia, worldwide, including but not limited to pharmaceutical corporations like Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Medigene, Arbormed, BioSyngen and others. In this role, he was/is further responsible for commercial technology transfer activities of his institute(s), including diabetes related patent portfolios of Helmholtz Munich as e. g. WO/2016/188932 A2 or WO/2017/194499 A1. Dr. Tschoep confirms that to the best of his knowledge none of the above funding sources were involved in the preparation of this paper.