Gestational diabetes and maternal obesity are associated with sex-specific changes in miRNA and target gene expression in the fetus.

BACKGROUND/

OBJECTIVES

Pregnancies complicated by gestational diabetes (GDM) or maternal obesity have been linked to the development of diabetes, obesity, and fatty liver disease later in life with sex-specific manifestations. Alterations in miRNA expression in offspring exposed to GDM and maternal obesity and effects on hepatic development are unknown. Here, we describe how exposure to maternal obesity in utero leads to sex-specific changes in miRNA and target gene expression in human fetal liver.

METHODS

Candidate miRNA expression was measured in second trimester amniotic fluid (AF) from women with GDM. Targets of differentially expressed miRNAs were determined and pathway enrichment of target genes was performed. MiRNA and target gene expression were measured in a separate cohort of second trimester primary human fetal hepatocytes (PHFH) exposed to maternal obesity via qPCR and western blot. All studies were IRB approved.

RESULTS

GDM-exposed AF had significant increases in miRNAs 199a-3p, 503-5p, and 1268a (fold change (FC) ≥ 1.5, p < 0.05). Female offspring-specific analysis showed enrichment in miRNAs 378a-3p, 885-5p, and 7-1-3p (p < 0.05). MiRNA gene targets were enriched in hepatic pathways. Key genes regulating de novo lipogenesis were upregulated in obesity-exposed PHFH, especially in males. Significantly altered miRNAs in GDM AF were measured in obese-exposed PHFH, with consistent increases in miRNAs 885-5p, 199-3p, 503-5p, 1268a, and 7-1-3p (FC ≥ 1.5, p < 0.05). Female PHFH exposed to maternal obesity had increased expression of miR-885-5p, miR-199-3p, miR-503-5p, miR-1268s, and miR-7-1-3p (p < 0.05), corresponding to decreased target genes expression for ABCA1, PAK4, and INSR. In male PHFHs, no miRNA changes were measured but there was increased expression of ABCA1, PAK4, and INSR (p < 0.05).

CONCLUSIONS

Our data suggest sex-specific changes in miRNA and gene expression in PHFH may be one mechanism contributing to the sexual dimorphism of metabolic disease in offspring exposed to GDM and maternal obesity in utero.