RNASeq - Epigenetic Activation of AKT1 Drives Metabolic Reprogramming in Advanced-Stage Lipedema: A Multi-Omics Study

Lipedema is a chronic, progressive adipose disorder affecting predominantly women, characterized by painful, symmetrical accumulation of subcutaneous fat in the limbs, and typically resistant to diet or exercise. The underlying pathophysiology of advanced stages remains poorly defined, and no validated biomarkers or molecular targets currently guide diagnosis or therapy. In this observational study, we employed a comprehensive multi-omics strategy to investigate the molecular and metabolic landscape of late-stage lipedema in female patients. Genome-wide DNA methylation profiling revealed over 5,000 differentially methylated CpG sites, impacting genes involved in receptor tyrosine kinase signaling, phospho-metabolism, and immune regulation. Transcriptome analysis identified pronounced downregulation of mitochondrial functions, including oxidative phosphorylation, the tricarboxylic acid (TCA) cycle, and fatty acid ß-oxidation, along with sirtuin pathway disruption and extracellular matrix remodelling. Integrative analysis pinpointed AKT1, a serine/threonine kinase involved in metabolism and survival, as a putative central regulator. A hypomethylated promoter region in AKT1 was associated with increased gene expression and protein phosphorylation. Metabolomic profiling of adipose tissue revealed altered levels of AKT1-linked metabolites, including L-arginine, NADP, ATP, guanosine, glycerol, and glutamate, suggesting coordinated dysregulation of amino acid metabolism, redox homeostasis, and energy production. Trans-omic network analysis further confirmed AKT1 as a central metabolic hub integrating epigenetic, transcriptomic, and metabolic alterations. Our findings identify epigenetically activated AKT1 signaling as a potential pathogenic driver of metabolic reprogramming in advanced lipedema and propose AKT1 as a candidate biomarker and therapeutic target to support disease stratification and intervention strategies.