The satiety adipokine Nesfatin-1/NUCB2 is expressed in human term trophoblast and placental mesenchymal stem cells and is increased during oxidative and ER stress (#217)
Nesfatin-1 is an 82 amino acid anorectic adipokine derived from the nucleobindin2 precursor protein (NUCB2). Via interaction with melanocortin 3/4 receptors in the hypothalamus, nesfatin-1 inhibits food intake and increases blood pressure in rodents. In humans nesfatin-1/NUCB2 is widely expressed, however, its expression in gestational tissues has not been previously reported. Here we demonstrate that nesfatin-1/NUCB2 protein is expressed in the highly-secretory syncytiotrophoblast of human term placenta and in the trophoblast cell lines JEG-3 and BeWo. Isolated mesenchymal stem cells from the chorionic membrane (CM-MSC) and chorionic villi (CV-MSC) also express NUCB2 at the mRNA level. Endoplasmic reticulum (ER) stress has recently been implicated in placental pathologies which can result in pre-eclampsia and intrauterine growth restriction. The NUCB2 promoter region contains cis-elements for transcriptional activation by ATF6, a transcription factor involved in the unfolded protein response. Using the chemical ER stressor tunicamycin and spliced XBP-1 as a marker of ER stress, we demonstrate that ER stress increases NUCB2 expression in JEG-3 and BeWo cells and in CM-MSC and CV-MSC. 24 hour treatment with non-cytotoxic doses of tunicamycin (0.9µg/ml) increases NUCB2 mRNA expression by 2.2 (+/-0.6) fold in the JEG-3 cell line and by 2.5 (+/-0.5) fold in the BeWo cell line. Both CM-MSC and CV-MSC were more sensitive to tunicamycin than were the choriocarcinoma cell lines and therefore a lower stressor dose was required. Tunicamycin (0.6µg/ml) - induced ER stress resulted in a 2.7 (+/-0.8) and 1.9 (+/-0.9) fold increase in NUCB2 transcription in CM-MSC and CV-MSC respectively. Collectively, these data indicate that NUCB2 is an ER-stress responsive gene expressed in term placenta and placental cell lines and MSC. Future work will investigate if nesfatin-1/NUCB2 is increased in tissues from pre-eclamptic pregnancies and other placental pathology where ER stress is evident.