Sleep Homeostasis Ensembles in the Hypothalamic PVN Reprogram Systemic Fuel Utilization via Adipose Lipolysis

While sleep homeostasis is fundamental, its causal contribution on systemic metabolism remains incompletely understood. By decoupling sleep homeostasis from circadian influences, this study identifies a previously unrecognized neural mechanism linking compensatory sleep to whole-body metabolism. Using a minimally confounded sleep homeostasis model, spatial transcriptomics revealed the paraventricular nucleus of the hypothalamus (PVN) as the most transcriptionally active region during rebound sleep. TRAP-tagging and functional manipulations demonstrated that PVN sleep-homeostasis ensemble neurons promote NREM sleep while simultaneously shifting whole-body energy utilization toward lipid oxidation. Activation of these neurons reduced respiratory exchange ratio, downregulated systemic glucose metabolism, and enhanced sympathetic-driven lipolysis in white adipose tissue (WAT), particularly inguinal depot. Stable isotope tracing confirmed suppressed glucose metabolic flux in WAT during recovery sleep. These findings uncover a neural substrate through which sleep homeostasis regulates peripheral energy balance, revealing a metabolic trade-off that may underlie the increased diabetes risk associated with sleep disruption.