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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE317867 | GEO | 2026/07/01

REPOSITORIES: GEO

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