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.
Highlights
Fetal growth restriction (FGR) is the second leading cause of perinatal death after prematurity and affects 3–7% of all pregnancies [1, 2]
Seven of the eighty-four unfolded protein response (UPR) molecules displayed significant differential transcription level; 6 were upregulated; and 1 was downregulated in the FGR fetal pancreas compared with the control. ese differentially expressed molecules could be assigned to five categories of UPR pathway according to molecular function, including transcription factor, endoplasmic reticulum-associated degradation, and regulation of translation, apoptosis and heat-shock protein (Figure 2(d))
Epidemiological and experimental studies have substantiated the proposed link between adverse intrauterine environments and adult diseases, such as T2DM and hyperglycemia. is study demonstrated that FGR fetus caused by a low-protein diet during pregnancy was characterized by reduced pancreatic islet numbers and size
Summary
Fetal growth restriction (FGR) is the second leading cause of perinatal death after prematurity and affects 3–7% of all pregnancies [1, 2]. It is becoming apparent that FGR has major impacts on the fetus, with negative effects on cardiovascular, metabolic, and neurological development. FGR increases the susceptibility to metabolic syndrome (type 2 diabetes mellitus (T2DM), obesity, and cardiovascular diseases) [4,5,6]. FGR fetuses have reduced circulating insulin levels, hyperglycemia, and impaired glucose tolerance [7]. Using a well-established rat models caused by low-protein (LP) diet, our previous work has suggested that maternal malnutrition leads to hyperglycemia and impaired glucose tolerance in FGR adult rats [8], consistent with other reports [9, 10]
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