Abstract
Stress can drive overconsumption of high-fat foods. The medial prefrontal cortex (mPFC) is implicated in such stress-eating, but the underlying circuit mechanisms remain unclear. Here, we show that mPFC projections to the lateral hypothalamus (LHA) are required for stress-induced fat intake in male mice. We find that mPFC-LHA stimulation in sated states increases fat intake. Social stress acutely engages mPFC-LHA neurons, and inhibiting this pathway selectively prevents stress-driven excess fat intake. Circuit mapping shows that mPFC neurons innervate GABAergic and glutamatergic LHA (LHAVGLUT2) neurons, but that social stress preferentially engages mPFC-LHAVGLUT2 neurons and causes plasticity at mPFC-LHAVGLUT2 synapses. Specifically, stress weakens mPFC synapses onto LHAVGLUT2 neurons that curtail food intake, while strengthening mPFC synapses onto midbrain-projecting LHAVGLUT2 neurons linked to stress-eating. We show that LHAVGLUT2 neurons are required downstream mPFC targets for transforming stress into heightened fat intake. Overall, we identify the mPFC-LHA as a multi-branched network, indispensable for stress-eating.
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All detailed outcomes of the statistical test are provided in Supplementary Data 1. Source Data are provided with this paper. Other data files are available from the corresponding author on request. Source data are provided with this paper.
Code availability
The location for the codes used for the analyses in the current study have been referenced in the Methods section of the manuscript.
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Acknowledgements
We thank Fabien Ducrocq, Salvatore Lecca, Manuel Mameli, and the entire Meye Lab for discussions and critical reading of the manuscript. We thank Zoë Bor and Luc Sangers for assistance in analysis, Jaimie Hak and Simone Duis for assistance with surgeries, Maarten Werkman and Doortje Knobbe for assistance with systemic injections, and Nicky van Kronenburg for assistance in mouse breeding. This work was supported by (to FJM) the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement 804089; ReCoDE), the NWO VIDI grant 203.102, and partially by the NWO Gravitation project BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (024.004.012), an Amsterdam UMC Fellowship to DR, and a Marie-Curie Individual Fellowship (CoMPOSE, grant agreement 898036) to RBP.
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L.F.S. performed and analysed all ex vivo electrophysiological recordings. K.L.K. performed the fiber photometric recordings, together with L.F.S. L.F.S. performed and analysed the following behavioral experiments: opto-stimulation of LHAVGLUT2-Peri-PVN, opto-stimulation of mPFC-LHAVGLUT2, combining with chemogenetic inhibition, opto-stimulation of mPFC TRAP ensemble, and restraint stress exposure. For these experiments, L.F.S. was further supported by F.J.M., W.D., and D.R. R.B.P. performed and analysed all other behavioral experiments, supported by A.A.C.B., A.S.J.N., and R.H. R.B.P. performed and analysed in vivo electrophysiological recordings. L.F.S., R.B.P., IW.-D., and M.C.M.L. performed stereotactic surgeries. FJM designed the study with R.B.P. and L.F.S. F.J.M. wrote the manuscript with L.F.S., R.A.H.A., R.B.P., and the help of all other authors.
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Supiot, L.F., Kooij, K.L., Du, W. et al. A prefrontal cortex-lateral hypothalamus circuit controls stress-driven increased food intake. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71073-z
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DOI: https://doi.org/10.1038/s41467-026-71073-z
