Histamine H3 receptors in the paraventricular thalamus link sleep loss to fat overconsumption

Sleep loss promotes obesity, yet the neural mechanisms linking disrupted sleep patterns to abnormal feeding behaviors remain unclear. By integrating the UK Biobank cohort analyses with mouse sleep restriction (SR) models, we demonstrate that insufficient sleep selectively increases high-fat diet (HFD) preference (HFDP), without affecting standard chow or high-sugar consumption. Whole-brain c-Fos mapping and in vitro electrophysiological techniques reveal reduced excitability of glutamatergic neurons in the paraventricular thalamus (PVT) following SR. Supportively, chemogenetic manipulations of PVT neurons bidirectionally regulate SR-induced HFDP. Further ultra-trace protein detection shows that histamine H3 receptor (H₃R) expression negatively correlates with overconsumption. SR triggers local histamine accumulation in the PVT, which downregulates H₃Rs via the β-arrestin pathway. Importantly, overexpressing PVT H₃Rs or inhibiting β-arrestin locally rescues the SR-induced HFDP. Collectively, our findings reveal PVT-H₃R signaling as a critical pathway converting circadian disruption to fat-specific hyperphagia, offering more therapeutic targets for precise body-weight management.