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

BACKGROUND

White adipose tissue (WAT) is a key endocrine organ regulating lipid and glucose homeostasis. Early metabolic disturbances may disrupt its endocrine function through epigenetic mechanisms; however, how DNA methylation contributes to prediabetes and its reversal remains largely unexplored.

OBJECTIVE

To characterize genome-wide DNA methylation changes in visceral WAT from 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, and FC drank a 10% fructose solution for 21 days followed by tap water for 49 days. Plasma parameters were measured and Whole Genome Bisulfite Sequencing was performed on visceral WAT to identify differential CpG methylation, followed by pathway enrichment and network analyses. RT-qPCR was used to evaluate gene expression.

RESULTS

Fructose intake induced a prediabetic phenotype, which was reversed by dietary normalization. In visceral WAT, 1151 differentially methylated CpG sites were identified and 330 genes enriched in oxidative phosphorylation and thermogenesis, key regulators of adipocyte endocrine and mitochondrial function. A stringent analysis showed a subset of CpG sites associated with Kdm4c, Ces1f, and Uxs1, whose expression was modified, suggesting functional implications for endocrine regulation of adipocyte metabolism. Notably, several methylation alterations persisted despite metabolic recovery, indicating incomplete epigenetic reversal.

CONCLUSIONS

Fructose-induced prediabetes produces DNA methylation changes in visceral white adipose tissue. Despite normalization of plasma parameters in the FC group, several epigenetic alterations persisted, highlighting their potential role in early metabolic disturbances leading to T2D.