Dysregulation in the Unfolded Protein Response in the FGR Rat Pancreas

Abstract

Accumulating evidence suggests that fetal growth restriction (FGR) leads to the development of diabetes mellitus in adults. The aim of this study was to investigate the effect of protein malnutrition in utero on the pancreatic unfolded protein response (UPR) pathway in FGR offspring. An FGR model was developed by feeding a low-protein diet to pregnant rats throughout gestation. Eighty-four UPR pathway components in the pancreas were investigated by quantitative PCR arrays and confirmed by qPCR and western blotting. Activating transcription factor (Atf4 and Atf6), herpud1, protein kinase R-like endoplasmic reticulum kinase (Perk), X-box binding protein 1 (Xbp1), and the phosphorylation of eIF2α were upregulated, while cyclic AMP-responsive element-binding protein 3-like protein was markedly downregulated in FGR fetuses compared with controls. Investigation in adult offspring revealed temporal changes, for most UPR factors restored to normal, except that dysregulation of Atf6 and Creb3l3 maintained until adulthood. Moreover, autophagy was suppressed in FGR fetal pancreas and may be associated with decreased activation of AMP-activated protein kinase (Ampk). Apoptosis regulators Bax and cleaved-caspase 3 and 9 were upregulated in FGR fetal pancreas. Given that islet size and number were decreased in FGR fetus, we speculated that the aberrant intrauterine milieu impaired UPR signaling in fetal pancreas development. Whether these alterations early in life contribute to the predisposition of FGR fetuses to adult metabolic disorders invites further exploration.

The Role of Cellular Stress in Intrauterine Growth Restriction and Postnatal Dysmetabolism

“…Examination of pancreata by transmission electron microscopy further revealed the presence of autophagosomes in islet -cells, while mTORC protein levels were also decreased relative to control offspring [83]. Conversely, another study found LC3BII and Beclin1 protein abundance to be decreased in the IUGR fetal pancreas following protein restriction [82]. These findings were not expected by the authors of the study; however, they speculated that autophagy may have been suppressed due to decreased phosphorylation of AMPK [82].…”

“…Conversely, another study found LC3BII and Beclin1 protein abundance to be decreased in the IUGR fetal pancreas following protein restriction [82]. These findings were not expected by the authors of the study; however, they speculated that autophagy may have been suppressed due to decreased phosphorylation of AMPK [82]. It was also noted that the whole pancreas was used for molecular analyses, and the authors acknowledged that the endocrine and exocrine pancreas are affected differently by the in utero environment.…”

“…Given that ER stress is linked to glucose intolerance and insulin resistance, it seems appropriate that IUGR offspring exhibit activation of the UPR in additional organs involved in glucose homeostasis. Much like the liver, gestational exposure to a low protein diet leads to activation of all three UPR pathways in the pancreas; however, this was exclusive to the fetal pancreas at ED20 [82]. Fetal pancreata displayed increased Atf4/6, protein kinase R-like endoplasmic reticulum kinase (PERK), Xbp-1, p-eIF2, and cAMP responsive element-binding protein-3-like 3 (Creb3l3), while adult offspring only had upregulation of Atf6 and Creb3l3 [82].…”

“…Much like the liver, gestational exposure to a low protein diet leads to activation of all three UPR pathways in the pancreas; however, this was exclusive to the fetal pancreas at ED20 [82]. Fetal pancreata displayed increased Atf4/6, protein kinase R-like endoplasmic reticulum kinase (PERK), Xbp-1, p-eIF2, and cAMP responsive element-binding protein-3-like 3 (Creb3l3), while adult offspring only had upregulation of Atf6 and Creb3l3 [82]. An additional study found that Grp78 was increased in fetal pancreatic islets following protein restriction, along with increased transcript and protein levels of CHOP [83].…”

The Role of Cellular Stress in Intrauterine Growth Restriction and Postnatal Dysmetabolism

“…Given that ER stress is linked to glucose intolerance and insulin resistance, it seems appropriate that IUGR offspring exhibit activation of the UPR in additional organs involved in glucose homeostasis. Much like the liver, gestational exposure to a low protein diet leads to activation of all three UPR pathways in the pancreas; however, this was exclusive to the fetal pancreas at ED20 [81]. Fetal pancreata displayed increased Atf4/6, protein kinase R-like endoplasmic reticulum kinase (PERK), Xbp-1, p-eIF2α, and cAMP responsive element-binding protein-3-like 3 (Creb3l3), while adult offspring only had upregulation of Atf6 and Creb3l3 [81].…”