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

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.