Maternal high-fat diet programs reproductive function of female offspring rat through IL-6-mediated regulation of Kiss1 gene methylation

Abstract

Maternal high-fat diet (HFD) is known to impair the reproductive function of female offspring, but the underlying epigenetic mechanisms of this developmental programming remain unclear. In this study, female rats were fed either a control diet (CD; 10 % kcal from fat) or an HFD (60 % kcal from fat) prior to and during gestation and lactation. After weaning, female offspring were randomly assigned to continue on either a CD or HFD, resulting in four groups: C/C, C/HF, HF/C, and HF/HF. Maternal HFD significantly reduced primordial follicle numbers, increased follicular atresia and granulosa cell apoptosis, and disrupted sex hormone levels in female offspring at 3 months of age. Female offspring from HFD-fed dams exhibited reduced Kiss1 gene expression and increased promoter methylation in both the ovaries and hypothalami. Additionally, the IL-6/STAT3 pathway was activated, and the expression of Ten-eleven translocation methylcytosine dioxygenase 2 (TET2), a key regulator of DNA demethylation, was downregulated. Post-weaning exposure to a normal diet partially attenuated these effects by 6 months of age. Furthermore, in vitro experiments demonstrated that IL-6/STAT3 signaling downregulated the expression of TET2 and Kisspeptin. Overall, our study demonstrates that maternal HFD consumption reduces TET2 expression in the ovaries and hypothalami of female offspring via the IL-6/STAT3 pathway, leading to Kiss1 promoter hypermethylation and a subsequent decrease in Kisspeptin levels. These findings highlight a potential epigenetic mechanism linking maternal diet to long-term reproductive toxicity in female offspring.

Keywords: Interleukin-6; Kiss1 gene; Maternal high-fat diet; Methylation; Ten-eleven translocation methylcytosine dioxygenase 2.