Pancreatic islets adapt to insulin resistance of pregnancy by up regulating β-cell mass and increasing insulin secretion. Previously, using a transgenic mouse with global, heterozygous deletion of prolactin receptor (Prlr+/−), we found Prlr signaling is important for this adaptation. However, since Prlr is expressed in tissues outside of islets as well as within islets and prolactin signaling affects β-cell development, to understand β-cell-specific effect of prolactin signaling in pregnancy, we generated a transgenic mouse with an inducible conditional deletion of Prlr from β-cells. Here, we found that β-cell-specific Prlr reduction in adult mice led to elevated blood glucose, lowed β-cell mass and blunted in vivo glucose-stimulated insulin secretion during pregnancy. When we compared gene expression profile of islets from transgenic mice with global (Prlr+/−) versus β-cell-specific Prlr reduction (βPrlR+/−), we found 95 differentially expressed gene, most of them down regulated in the Prlr+/− mice in comparison to the βPrlR+/− mice, and many of these genes regulate apoptosis, synaptic vesicle function and neuronal development. Importantly, we found that islets from pregnant Prlr+/− mice are more vulnerable to glucolipotoxicity-induced apoptosis than islets from pregnant βPrlR+/− mice. These observations suggest that down regulation of prolactin action during pregnancy in non-β-cells secondarily and negatively affect β-cell gene expression, and increased β-cell susceptibility to external insults.
Placental abnormalities have been sporadically implicated as a source of developmental heart defects. Yet it remains unknown how often the placenta is at the root of congenital heart defects (CHDs), and what the cellular mechanisms are that underpin this connection. Here, we selected three mouse mutant lines, Atp11a, Smg9 and Ssr2, that presented with placental and heart defects in a recent phenotyping screen, resulting in embryonic lethality. To dissect phenotype causality, we generated embryo- and trophoblast-specific conditional knockouts for each of these lines. This was facilitated by the establishment of a new transgenic mouse, Sox2-Flp, that enables the efficient generation of trophoblast-specific conditional knockouts. We demonstrate a strictly trophoblast-driven cause of the CHD and embryonic lethality in one of the three lines (Atp11a) and a significant contribution of the placenta to the embryonic phenotypes in another line (Smg9). Importantly, our data reveal defects in the maternal blood-facing syncytiotrophoblast layer as a shared pathology in placentally induced CHD models. This study highlights the placenta as a significant source of developmental heart disorders, insights that will transform our understanding of the vast number of unexplained congenital heart defects.
Fetal growth restriction (FGR) is a pregnancy condition in which fetal growth is suboptimal for gestation, and this population is at increased risk for type 2 diabetes as adults. In humans, maternal malnutrition and placental insufficiency are the most common causes of FGR, and both result in fetal undernutrition. We hypothesized that maternal nutrient restriction (MNR) in mice will cause FGR and alter glucose metabolism in adult offspring. Pregnant CD-1 mice were subjected to MNR (70% of average ad libitum) or control (ad libitum) from E6.5 to birth. Following birth, mice were fostered by mothers on ad libitum feeds. Weight, blood glucose, glucose tolerance and tissue-specific insulin sensitivity were assessed in male offspring. MNR resulted in reduced fetal sizes but caught up to controls by 3 days postnatal age. As adults, glucose intolerance was detected in 19% of male MNR offspring. At 6 months, liver size was reduced (P = 0.01), but pAkt-to-Akt ratios in response to insulin were increased 2.5-fold relative to controls (P = 0.004). These data suggest that MNR causes FGR and long-term glucose intolerance in a population of male offspring similar to human populations. This mouse model can be used to investigate the impacts of FGR on tissues of importance in glucose metabolism.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.