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

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.
Competing Interests: Declaration of interests M.H.T. participated in a scientific advisory board meeting of ERX Pharmaceuticals, Inc. (Cambridge, MA, USA) in 2019. He was a member of the Research Cluster Advisory Panel (ReCAP) of the Novo Nordisk Foundation between 2017 and 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 consulted for Böhringer Ingelheim Pharma GmbH & Co. KG (2020). He delivered a scientific lecture for Sanofi-Aventis Deutschland GmbH in 2020. R.G.J. is a scientific advisor to Servier, Agios Pharmaceuticals, and is a shareholder and member of the scientific advisory board of Immunomet Therapeutics.
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