Background: Endoplasmic reticulum (ER) is the site where proteins are folded. Perturbation of ER homeostasis activates a set of ER-to-nucleus signaling reactions known as the unfolded protein response (UPR). Metabolic stress causes UPR activation which contributes to the development of insulin resistance and metabolic syndrome. As UPR can be activated by nutrient and oxygen starvation, we postulated that intrauterine growth restriction may trigger UPR signaling and thereby contribute to the metabolic risk of IUGR subjects.
Objective and hypotheses: i) to evaluate liver UPR and ii) to determine the functional consequences of UPR in IUGR rat pups.
Method: Sprague-Dawley pregnant rats underwent surgery for uterine artery ligation at day 19 of gestation. Approximately 8 h after delivery, pups were weighed and killed. Tissue was immediately harvested and stored at <80°C. The expression of genes that regulate liver UPR and their metabolic targets were investigated in 14 SHAM and 14 IUGR pups.
Results: IUGR animals had significantly lower birth weight than controls (P<0.001). No significant differences were observed in blood glucose and insulin levels at birth. IUGR animals showed significantly higher NEFA blood levels (P<0.001). A significant increased expression of XBP1s mRNA (P<0.01), Erdj4 mRNA (P<0.05) and Bip mRNA (P<0.05) was observed in liver of IUGR pups. In IUGR pups the gene expression of Pck1 and G6pc (gluconeogenesis genes) and Acc2, Dgat2 and Scd1 (lipogenesis genes) was significantly upregulated (P<0.05).
Conclusion: We document hepatic UPR activation by uteroplacental insufficiency in newborn animals. Specifically, the IRE1α and ATF6 UPR signalling branches display higher levels of activation. In IUGR newborn pups, UPR activation correlates with the increased levels of mRNAs encoding lipogenic and gluconeogenic enzymes. Our findings suggest that hepatic ER stress/UPR signalling may play a role in the metabolic risk associated to intrauterine growth retardation.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology