Background: Endoplasmic reticulum (ER) is the site where proteins are folded in the cell. Metabolic stress alters ER homeostasis and activates the unfolded protein response (UPR), which contributes to the development of insulin resistance and metabolic syndrome.
Objective and hypotheses: To longitudinally evaluate liver UPR and its functional consequences in an animal model of IUGR followed from birth to adulthood.
Method: On day 19 of gestation, Sprague-Dawley pregnant rats underwent ligation of both uterine arteries. The offspring was either weighed and killed at 8 h after delivery or followed up to 105 d. Glucose and insulin concentrations were measured. Glucose tolerance test was performed at 105 d. The expression of genes that regulate liver UPR and their metabolic targets were investigated in 11 SHAM and 10 IUGR male rats at 105 d.
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 and 105 days. In the liver of IUGR male rats a significant reduction of insulin receptor, Akt and pAKT protein levels was observed (P<0.05). The liver expression of XBP1s mRNA was reduced (P<0.01) whereas the expression of PERK and Asns was increased (P<0.05). Western blot analysis confirmed UPR activation of IRE1a, PERK and ATF6 branches. A significant correlation between Xbp1s and pAkt levels was found (P<0.01). No significant differences were observed in gene expression of Pck1 and G6pc (gluconeogenesis related genes) and Acc2, Dgat2 and Scd1 (lipogenesis related genes). Histological examination of liver tissues showed focal steatosis in IUGR male rats.
Conclusion: The offspring of mothers exposed to uteroplacental insufficiency show hepatic UPR activation. In parallel with IRE1alpha, ATF6 and PERK branch activation an impairment of glucose tolerance and focal hepatic steatosis were observed. These findings suggest that hepatic ER stress/UPR signalling may play a role in the long-term metabolic risk associated with IUGR.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology