Maternal undernutrition around the time of conception is associated with an increased risk of insulin resistance in adulthood. We determined the effect of maternal undernutrition in the periconceptional period (PCUN, i.e., 60 days prior to 6 days after conception) and the preimplantation period (PIUN, i.e., 0-6 days after conception) on mRNA expression and protein abundance of key insulin-signaling molecules as well as the global microRNA expression in quadriceps muscle of singleton and twin fetal sheep in late gestation. In singleton fetuses, exposure to PCUN resulted in lower protein abundance of PIK3CB (P < 0.01), PRKCZ (P < 0.05), and pPRKCZ (Thr410) (P < 0.05) in skeletal muscle compared to controls. In PIUN singletons, there was a higher protein abundance of IRS1 (P < 0.05), PDPK1 (P < 0.05), and SLC2A4 (P < 0.05) compared to controls. In twins, PCUN resulted in higher protein abundance of IRS1 (P < 0.05), AKT2 (P < 0.05), PDPK1 (P < 0.05), and PRKCZ (P < 0.001), while PIUN also resulted in higher protein abundance of IRS1 (P < 0.05), PRKCZ (P < 0.001), and SLC2A4 (P < 0.05) in fetal muscle compared to controls. There were specific patterns of the types and direction of changes in the expression of 22 microRNAs in skeletal muscle after exposure to PCUN or PIUN and clear differences in these patterns between singleton and twin pregnancies. These findings provide evidence that maternal undernutrition around the time of conception induces changes in the expression of microRNAs, which may play a role in altering the abundance of the key insulin-signaling molecules in skeletal muscle and in the association between PCUN undernutrition and insulin resistance in adult life.
-This study aimed to determine whether exposure of the oocyte and/or embryo to maternal undernutrition results in the later programming of insulin action in the liver and factors regulating gluconeogenesis. To do this, we collect livers from singleton and twin fetal sheep that were exposed to periconceptional (PCUN; Ϫ60 to 7 days) or preimplantation (PIUN; 0 -7 days) undernutrition at 136 -138 days of gestation (term ϭ 150 days). The mRNA and protein abundance of insulin signaling and gluconeogenic factors were then quantified using qRT-PCR and Western blotting, respectively, and global microRNA expression was quantified using deep sequencing methodology. We found that hepatic PEPCK-C mRNA (P Ͻ 0.01) and protein abundance and the protein abundance of IRS-1 (P Ͻ 0.01), p110 (P Ͻ 0.05), PTEN (P Ͻ 0.05), CREB (P Ͻ 0.01), and pCREB (Ser 133 ; P Ͻ 0.05) were decreased in the PCUN and PIUN singletons. In contrast, hepatic protein abundance of IRS-1 (P Ͻ 0.01), p85 (P Ͻ 0.01), p110 (P Ͻ 0.001), PTEN (P Ͻ 0.01), Akt2 (P Ͻ 0.01), p-Akt (Ser 473 ; P Ͻ 0.01), and p-FOXO-1 (Thr24) (P Ͻ 0.01) was increased in twins. There was a decrease in PEPCK-C mRNA (P Ͻ 0.01) but, paradoxically, an increase in PEPCK-C protein (P Ͻ 0.001) in twins. Both PCUN and PIUN altered the hepatic expression of 23 specific microRNAs. We propose that the differential impact of maternal undernutrition in the presence of one or two embryos on mRNAs and proteins involved in the insulin signaling and gluconeogenesis is explained by changes in the expression of a suite of specific candidate microRNAs.pregnancy; nutrition; fetus; epigenetic IT HAS BEEN DEMONSTRATED in a range of epidemiological and experimental studies that exposure of the oocyte, embryo, or fetus to a range of environmental stressors, including poor maternal nutrition, results in poor metabolic and cardiovascular outcomes in postnatal life (8,9,13,22,25,41,42,53,56). In sheep, maternal undernutrition from 60 days before to 30 days after conception resulted in an impairment of the insulin and glucose responses to a glucose tolerance test at 10 mo after birth (49). The effects of exposure to maternal undernutrition during early gestation were also more pronounced in singleton than in twin offspring. However, it is not known whether exposure to maternal undernutrition limited to around the time of conception alone is sufficient to program changes in the insulin-signaling pathway in tissues of metabolic importance such as the liver or whether there is a differential impact of maternal undernutrition in the periconceptional period in singletons and twins.Insulin acts through the insulin receptor (IR), which is stabilized by caveolin-1 (Cav-1), resulting in a series of activations by phosphorylation of the insulin receptor substrate-1 (IRS-1) or -2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), and conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). Conversion of PIP2 to PIP3 is negatively regulated by phosphatase and tensin homolog (...
Exposure to poor maternal nutrition around the time of conception results in an early prepartum activation of the fetal pituitary-adrenal axis and in increased adrenal growth and stress response after birth associated with epigenetic changes in a differentially methylated region (DMR) of adrenal IGF2/H19. We have determined the effects of maternal undernutrition during the periconceptional period (PCUN: 70% of control intake from 60 days before until 6 days after conception) and early preimplantation period (PIUN: 70% of control intake for 6 days after conception) on fetal plasma ACTH and cortisol concentrations and fetal adrenal ACTHR, StAR, 3βHSD, CYP11B, CYP17, TGFβ1, IGF1, IGF1R, IGF2, and IGF2R mRNA expression and the methylation level of sites within the DMRs of IGF2/H19 and IGF2R in the adrenal of twin and singleton fetuses at 136-138 days gestation. Being a twin resulted in a delayed prepartum increase in fetal ACTH and in a lower cortisol response to CRH in the control but not PCUN and PIUN groups. PCUN, but not PIUN, resulted in an increase in adrenal weight and CYP17 expression in singletons, a decrease in adrenal IGF2 expression in singletons, and an increase in adrenal IGF2R expression in both twins and singletons. IGF2/H19 and IGF2R DMR methylation levels and ACTHR expression were lower in the twin adrenal. Thus, exposure of the oocyte and embryo to maternal undernutrition or to the environment of a twin pregnancy have differential effects on epigenetic and other factors that regulate fetal adrenal growth and IGF2 and IGF2R expression.
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