Fructose-induced prediabetes causes persistent DNA methylation changes in white adipose tissue despite metabolic normalization

DUMRAUF B; MENCUCCI, MV; LACUNZA E; ABBA M; FLORES LE; MAIZTEGUI B; GAGLIARDINO JJ; FRANCINI F; ROMAN L

MOLECULAR AND CELLULAR ENDOCRINOLOGY.

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2026

0303-7207

Background: White adipose tissue (WAT) is a key endocrine organ regulating lipid andglucose homeostasis. Early metabolic disturbances may disrupt its endocrine functionthrough epigenetic mechanisms; however, how DNA methylation contributes toprediabetes and its reversal remains largely unexplored.Objective: To characterize genome-wide DNA methylation changes in visceral WATfrom prediabetic rats and after dietary normalization.Methods: Male rats were fed a standard diet for 70 days and divided into 3 groups:Control (C) received tap water, Fructose (F) consumed a 10% fructose solution, andFC drank a 10% fructose solution for 21 days followed by tap water for 49 days.Plasma parameters were measured and Whole Genome Bisulfite Sequencing wasperformed on visceral WAT to identify differential CpG methylation, followed bypathway enrichment and network analyses. RT-qPCR was used to evaluate geneexpression.Results: Fructose intake induced a prediabetic phenotype, which was reversed bydietary normalization. In visceral WAT, 1,151 differentially methylated CpG sites wereidentified and 330 genes enriched in oxidative phosphorylation and thermogenesis, keyregulators of adipocyte endocrine and mitochondrial function. A stringent analysisshowed a subset of CpG sites associated with Kdm4c, Ces1f, and Uxs1, whoseexpression was modified, suggesting functional implications for endocrine regulation ofadipocyte metabolism. Notably, several methylation alterations persisted despitemetabolic recovery, indicating incomplete epigenetic reversal.Conclusions: Fructose-induced prediabetes produces DNA methylation changes invisceral white adipose tissue. Despite normalization of plasma parameters in the FCgroup, several epigenetic alterations persisted, highlighting their potential role in earlymetabolic disturbances leading to T2D.