Epigenetic Signature of the Metastable Epiallele VTRNA2-1: Adipose Dysfunction and Suboptimal Bariatric Outcomes.

Abstract

VTRNA2-1 is a metastable epiallele whose methylation is associated with metabolic homeostasis via PKR-mediated inflammation and adipocyte function. We aimed to determine whether preoperative VTRNA2-1 promoter methylation in peripheral blood predicts long-term excess weight loss (%EWL) after bariatric surgery. We explored transcriptional signatures in adipose tissue to clarify the relationship between early-life epigenetic imprinting on adult metabolic plasticity and surgical outcomes in patients with severe obesity. In the OCEAN prospective registry (2011-2024), 179 adults underwent bariatric surgery. Peripheral blood DNA VTRNA2-1 methylation was classified as hypo-, intermediate, or hyper-methylated. %EWL was recorded at 3, 6, 12, and 24 months. Adipose tissue was assayed for IL13, PRDM16, and related transcripts. VTRNA2-1 methylation showed a bimodal distribution, differing significantly from controls (p = 0.002). Hypermethylated patients had lower VTRNA2-1 expression (p < 0.001) and greater %EWL at 12 (67.8% ± 19.1% vs. 61.8% ± 17.5%; p = 0.047) and 24 months (68.7% ± 21.9% vs. 60.4% ± 19.3%; p = 0.040). The hypomethylated group maintained a stable weight loss plateau between 12 and 24 months. Hypomethylation was associated with nominally higher IL13 and PRDM16 mRNA in adipose tissue (exploratory; uncorrected p < 0.05). VTRNA2-1 methylation status is associated with predictable variations and offers potential for preoperative risk stratification and personalized therapeutic strategies in managing severe obesity.