A UBE3A‐UTX Proteostasis‐Epigenetic Axis Governs Hypothalamic Energy Homeostasis

Energy homeostasis requires integration of metabolic and stress signals within hypothalamic circuits, yet the role of neuronal proteostasis remains unclear. Ubiquitin protein ligase E3A (UBE3A) regulates the stability of lysine demethylase 6A (KDM6A), also known as ubiquitously transcribed tetratricopeptide repeat containing, X chromosome (UTX). Hypothalamic neuronal deletion of Ube3a results in hyperphagia, obesity, hyperleptinemia, and impaired glucose homeostasis under high-fat diet conditions; selective deletion in agouti-related peptide (AgRP) neurons is sufficient to recapitulate these phenotypes. UBE3A promotes UTX degradation, whereas UBE3A loss stabilizes UTX and decreases repressive histone H3 lysine 27 trimethylation (H3K27me3). Integrated transcriptomic and epigenomic analyses implicate UTX and activating transcription factor 4 (ATF4) in altered endoplasmic reticulum (ER) stress-responsive transcriptional programs, although their causal contribution to the metabolic phenotype remains to be established. Treatment with GSK-J4, an inhibitor of KDM6-family demethylases, increases hypothalamic H3K27me3 levels and improves metabolic outcomes in Ube3a-deficient mice, although the specific contribution of hypothalamic UTX inhibition to these effects remains to be established. These findings support a link between neuronal proteostasis, chromatin regulation, and systemic metabolic homeostasis and warrant further investigation of the relevance of UTX-associated pathways to metabolic dysfunction in a subset of individuals with Angelman syndrome.