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Diabetes Aug 2016β-Cell proliferation and expansion during pregnancy are crucial for maintaining euglycemia in response to increased metabolic demands placed on the mother. Prolactin...
β-Cell proliferation and expansion during pregnancy are crucial for maintaining euglycemia in response to increased metabolic demands placed on the mother. Prolactin and placental lactogen signal through the prolactin receptor (PRLR) and contribute to adaptive β-cell responses in pregnancy; however, the in vivo requirement for PRLR signaling specifically in maternal β-cell adaptations remains unknown. We generated a floxed allele of Prlr, allowing conditional loss of PRLR in β-cells. In this study, we show that loss of PRLR signaling in β-cells results in gestational diabetes mellitus (GDM), reduced β-cell proliferation, and failure to expand β-cell mass during pregnancy. Targeted PRLR loss in maternal β-cells in vivo impaired expression of the transcription factor Foxm1, both G1/S and G2/M cyclins, tryptophan hydroxylase 1 (Tph1), and islet serotonin production, for which synthesis requires Tph1. This conditional system also revealed that PRLR signaling is required for the transient gestational expression of the transcription factor MafB within a subset of β-cells during pregnancy. MafB deletion in maternal β-cells also produced GDM, with inadequate β-cell expansion accompanied by failure to induce PRLR-dependent target genes regulating β-cell proliferation. These results unveil molecular roles for PRLR signaling in orchestrating the physiologic expansion of maternal β-cells during pregnancy.
Topics: Animals; Cell Proliferation; Cells, Cultured; Cyclin A2; Cyclin B1; Cyclin B2; Cyclin D1; Cyclin D2; Diabetes, Gestational; Female; Forkhead Box Protein M1; Insulin; Insulin-Secreting Cells; MafB Transcription Factor; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pregnancy; Receptors, Prolactin; Serotonin; Signal Transduction; Tryptophan Hydroxylase
PubMed: 27217483
DOI: 10.2337/db15-1527 -
Biology of Reproduction Sep 2015Pregnancy is often viewed as a conflict between the fetus and mother over metabolic resources. Insulin resistance occurs in mothers during pregnancy but does not...
Pregnancy Hyperglycemia in Prolactin Receptor Mutant, but Not Prolactin Mutant, Mice and Feeding-Responsive Regulation of Placental Lactogen Genes Implies Placental Control of Maternal Glucose Homeostasis.
Pregnancy is often viewed as a conflict between the fetus and mother over metabolic resources. Insulin resistance occurs in mothers during pregnancy but does not normally lead to diabetes because of an increase in the number of the mother's pancreatic beta cells. In mice, this increase is dependent on prolactin (Prl) receptor signaling but the source of the ligand has been unclear. Pituitary-derived Prl is produced during the first half of pregnancy in mice but the placenta produces Prl-like hormones from implantation to term. Twenty-two separate mouse genes encode the placenta Prl-related hormones, making it challenging to assess their roles in knockout models. However, because at least four of them are thought to signal through the Prl receptor, we analyzed Prlr mutant mice and compared their phenotypes with those of Prl mutants. We found that whereas Prlr mutants develop hyperglycemia during gestation, Prl mutants do not. Serum metabolome analysis showed that Prlr mutants showed other changes consistent with diabetes. Despite the metabolic changes, fetal growth was normal in Prlr mutants. Of the four placenta-specific, Prl-related hormones that have been shown to interact with the Prlr, their gene expression localizes to different endocrine cell types. The Prl3d1 gene is expressed by trophoblast giant cells both in the labyrinth layer, sitting on the arterial side where maternal blood is highest in oxygen and nutrients, and in the junctional zone as maternal blood leaves the placenta. Expression increases during the night, though the increase in the labyrinth is circadian whereas it occurs only after feeding in the junctional zone. These data suggest that the placenta has a sophisticated endocrine system that regulates maternal glucose metabolism during pregnancy.
Topics: Animals; Blood Glucose; Blood Pressure; Circadian Rhythm; Feeding Behavior; Female; Glucose; Homeostasis; Hyperglycemia; Male; Mice; Mice, Inbred C57BL; Mutation; Placenta; Placental Lactogen; Pregnancy; Prolactin; Receptors, Prolactin; Trophoblasts
PubMed: 26269505
DOI: 10.1095/biolreprod.115.132431 -
PloS One 2020The placenta, a tissue that is metabolically active and rich in mitochondria, forms a critical interface between the mother and developing fetus. Oxidative stress within...
The placenta, a tissue that is metabolically active and rich in mitochondria, forms a critical interface between the mother and developing fetus. Oxidative stress within this tissue, derived from the dysregulation of reactive oxygen species (ROS), has been linked to a number of adverse fetal outcomes. While such outcomes have been associated with mitochondrial dysfunction, the causal role of mitochondrial dysfunction and mitochondrially generated ROS in altering the process of placentation remains unclear. In this study, mitochondrial complex I activity was attenuated using 10 nM rotenone to induce cellular oxidative stress by increasing mitochondrial ROS production in the BeWo choriocarcinoma cell line. Increased mitochondrial ROS resulted in a significant decrease in the transcripts which encode for proteins associated with fusion (GCM1, ERVW-1, and ERVFRD-1) resulting in a 5-fold decrease in the percentage of BeWo fusion. This outcome was associated with increased indicators of mitochondrial fragmentation, as determined by decreased expression of MFN2 and OPA1 along with an increase in a marker of mitochondrial fission (DRP1). Importantly, increased mitochondrial ROS also resulted in a 5.0-fold reduction of human placental lactogen (PL) and a 4.4-fold reduction of insulin like growth factor 2 (IGF2) transcripts; hormones which play an important role in regulating fetal growth. The pre-treatment of rotenone-exposed cells with 5 mM N-acetyl cysteine (NAC) resulted in the prevention of these ROS mediated changes in BeWo function and supports a central role for mitochondrial ROS signaling in the maintenance and function of the materno-fetal interface.
Topics: Cell Fusion; Cells, Cultured; Female; Humans; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Placental Hormones; Pregnancy; Reactive Oxygen Species; Rotenone; Signal Transduction; Trophoblasts
PubMed: 32092105
DOI: 10.1371/journal.pone.0229332 -
Cancer Research Apr 2017Poor prognosis of ovarian cancer, the deadliest of the gynecologic malignancies, reflects major limitations associated with detection and diagnosis. Current methods lack...
Poor prognosis of ovarian cancer, the deadliest of the gynecologic malignancies, reflects major limitations associated with detection and diagnosis. Current methods lack high sensitivity to detect small tumors and high specificity to distinguish malignant from benign tissue, both impeding diagnosis of early and metastatic cancer stages and leading to costly and invasive surgeries. Tissue microarray analysis revealed that >98% of ovarian cancers express the prolactin receptor (PRLR), forming the basis of a new molecular imaging strategy. We fused human placental lactogen (hPL), a specific and tight binding PRLR ligand, to magnetic resonance imaging (gadolinium) and near-infrared fluorescence imaging agents. Both in tissue culture and in mouse models, these imaging bioconjugates underwent selective internalization into ovarian cancer cells via PRLR-mediated endocytosis. Compared with current clinical MRI techniques, this targeted approach yielded both enhanced signal-to-noise ratio from accumulation of signal via selective internalization and improved specificity conferred by PRLR upregulation in malignant ovarian cancer. These features endow PRLR-targeted imaging with the potential to transform ovarian cancer detection. .
Topics: Animals; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Endocytosis; Female; Gadolinium DTPA; Humans; Magnetic Resonance Imaging; Mice; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Placental Lactogen; Prolactin; Receptors, Prolactin; Sensitivity and Specificity; Tissue Array Analysis
PubMed: 28202518
DOI: 10.1158/0008-5472.CAN-16-1454 -
American Journal of Physiology.... Aug 2014In normal pregnancy, cortisol increases; however, further pathological increases in cortisol are associated with maternal and fetal morbidities. These experiments were...
In normal pregnancy, cortisol increases; however, further pathological increases in cortisol are associated with maternal and fetal morbidities. These experiments were designed to test the hypothesis that increased maternal cortisol would increase maternal glucose concentrations, suppress fetal growth, and impair neonatal glucose homeostasis. Ewes were infused with cortisol (1 mg·kg(-1)·day(-1)) from day 115 of gestation to term; maternal glucose, insulin, ovine placental lactogen, estrone, progesterone, nonesterified free fatty acids (NEFA), β-hydroxybutyrate (BHB), and electrolytes were measured. Infusion of cortisol increased maternal glucose concentration and slowed the glucose disappearance after injection of glucose; maternal infusion of cortisol also increased the incidence of fetal death at or near parturition. The design of the study was altered to terminate the study prior to delivery, and post hoc analysis of the data was performed to test the hypothesis that maternal metabolic factors predict the fetal outcome. In cortisol-infused ewes that had stillborn lambs, plasma insulin was increased relative to control ewes or cortisol-infused ewes with live lambs. Maternal cortisol infusion did not alter maternal food intake or plasma NEFA, BHB, estrone, progesterone or placental lactogen concentrations, and it did not alter fetal body weight, ponderal index, or fetal organ weights. Our study suggests that the adverse effect of elevated maternal cortisol on pregnancy outcome may be related to the effects of cortisol on maternal glucose homeostasis, and that chronic maternal stress or adrenal hypersecretion of cortisol may create fetal pathophysiology paralleling some aspects of maternal gestational diabetes.
Topics: Animals; Blood Glucose; Cushing Syndrome; Diabetes, Gestational; Disease Models, Animal; Energy Metabolism; Female; Fetal Blood; Fetal Death; Gestational Age; Homeostasis; Hydrocortisone; Hyperglycemia; Infusions, Intravenous; Insulin; Maternal Exposure; Placenta; Pregnancy; Sheep; Stillbirth; Time Factors
PubMed: 24920731
DOI: 10.1152/ajpregu.00530.2013 -
The Journal of Clinical Endocrinology... Dec 2014Thyroid hormone (TH) is essential for normal development; therefore, disruption of TH action by a number of industrial chemicals is critical to identify. Several...
CONTEXT
Thyroid hormone (TH) is essential for normal development; therefore, disruption of TH action by a number of industrial chemicals is critical to identify. Several chemicals including polychlorinated biphenyls are metabolized by the dioxin-inducible enzyme CYP1A1; some of their metabolites can interact with the TH receptor. In animals, this mechanism is reflected by a strong correlation between the expression of CYP1A1 mRNA and TH-regulated mRNAs. If this mechanism occurs in humans, we expect that CYP1A1 expression will be positively correlated with the expression of genes regulated by TH.
OBJECTIVE
The objective of the study was to test the hypothesis that CYP1A1 mRNA expression is correlated with TH-regulated mRNAs in human placenta.
METHODS
One hundred sixty-four placental samples from pregnancies with no thyroid disease were obtained from the GESTE study (Sherbrooke, Québec, Canada). Maternal and cord blood TH levels were measured at birth. The mRNA levels of CYP1A1 and placental TH receptor targets [placental lactogen (PL) and GH-V] were quantitated by quantitative PCR.
RESULTS
CYP1A1 mRNA abundance varied 5-fold across 132 placental samples that had detectable CYP1A1 mRNA. CYP1A1 mRNA was positively correlated with PL (r = 0.64; P < .0001) and GH-V (P < .0001, r = 0.62) mRNA. PL and GH-V mRNA were correlated with each other (r = 0.95; P < .0001), suggesting a common activator. The mRNAs not regulated by TH were not correlated with CYP1A1 expression.
CONCLUSIONS
CYP1A1 mRNA expression is strongly associated with the expression of TH-regulated target gene mRNAs in human placenta, consistent with the endocrine-disrupting action of metabolites produced by CYP1A1.
Topics: Adult; Cell Line; Cytochrome P-450 CYP1A1; Dioxins; Endocrine Disruptors; Female; Fetal Blood; Gene Expression Regulation, Enzymologic; Human Growth Hormone; Humans; Placenta; Placental Lactogen; Pregnancy; Smoking; Thyroid Hormones
PubMed: 25299844
DOI: 10.1210/jc.2014-2629 -
International Journal of Molecular... Jul 2021Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the...
Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the physiological consequences of CSH RNA interference (RNAi), the trophectoderm of hatched blastocysts (nine days of gestational age; dGA) was infected with a lentivirus expressing either a scrambled control or CSH-specific shRNA, prior to transfer into synchronized recipient sheep. At 90 dGA, umbilical hemodynamics and fetal measurements were assessed by Doppler ultrasonography. At 120 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies with the HO transplacental diffusion technique at 130 dGA. Nutrient uptake rates were determined and tissues were subsequently harvested at necropsy. CSH RNAi reduced ( ≤ 0.05) both fetal and uterine weights as well as umbilical blood flow (mL/min). This ultimately resulted in reduced ( ≤ 0.01) umbilical IGF1 concentrations, as well as reduced umbilical nutrient uptakes ( ≤ 0.05) in CSH RNAi pregnancies. CSH RNAi also reduced ( ≤ 0.05) uterine nutrient uptakes as well as uteroplacental glucose utilization. These data suggest that CSH is necessary to facilitate adequate blood flow for the uptake of oxygen, oxidative substrates, and hormones essential to support fetal and uterine growth.
Topics: Animals; Blastocyst; Female; Fetal Blood; Fetal Growth Retardation; Fetus; Gestational Age; Glucose; Hemodynamics; Insulin-Like Growth Factor I; Male; Nutrients; Placenta; Placental Lactogen; Pregnancy; RNA Interference; RNA, Small Interfering; Sheep; Signal Transduction; Ultrasonography, Doppler; Uterus
PubMed: 34360913
DOI: 10.3390/ijms22158150 -
Endocrine Aug 2014Prolactin (PRL) and placental lactogen stimulate beta cell replication and insulin production in vitro and in vivo. The molecular mechanisms by which lactogens promote...
Prolactin (PRL) and placental lactogen stimulate beta cell replication and insulin production in vitro and in vivo. The molecular mechanisms by which lactogens promote beta cell expansion are unclear. We treated rat insulinoma cells with a PRL receptor (PRLR) siRNA to determine if PRLR signaling is required for beta cell DNA synthesis and cell survival and to identify beta cell cycle genes whose expression depends upon lactogen action. Effects of PRLR knockdown were compared with those of PRL treatment. PRLR knockdown (-80 %) reduced DNA synthesis, increased apoptosis, and inhibited expression of cyclins D2 and B2, IRS-2, Tph1, and the anti-apoptotic protein PTTG1; p21 and BCL6 mRNAs increased. Conversely, PRL treatment increased DNA synthesis, reduced apoptosis, and enhanced expression of A, B and D2 cyclins, CDK1, IRS-2, FoxM1, BCLxL, and PTTG1; BCL6 declined. PRLR signaling is required for DNA synthesis and survival of rat insulinoma cells. The effects of lactogens are mediated by down-regulation of cell cycle inhibitors (BCL6, p21) and induction of A, B, and D2 cyclins, IRS-2, Tph1, FoxM1, and the anti-apoptotic proteins BCLxL and PTTG1.
Topics: Animals; Apoptosis; Cell Count; Cell Line, Tumor; Cyclins; DNA; Down-Regulation; Gene Expression; Insulin-Secreting Cells; Insulinoma; Pancreatic Neoplasms; RNA, Small Interfering; Rats; Receptors, Prolactin; Signal Transduction
PubMed: 24114406
DOI: 10.1007/s12020-013-0073-1 -
Reproductive Sciences (Thousand Oaks,... May 2015The effects of endogenous cortisol on binucleate cells (BNCs), which promote fetal growth, may be mediated by glucocorticoid receptors (GRs), and exposure to...
The effects of endogenous cortisol on binucleate cells (BNCs), which promote fetal growth, may be mediated by glucocorticoid receptors (GRs), and exposure to dexamethasone (DEX) in early pregnancy stages of placental development might modify this response. In this article, we have investigated the expression of GR as a determinant of these responses. Pregnant ewes carrying singleton fetuses (n = 119) were randomized to control (2 mL saline/ewe) or DEX-treated groups (intramuscular injections of 0.14 mg/kg ewe weight per 12 hours) at 40 to 41 days of gestation (dG). Placental tissue was collected at 50, 100, 125, and 140 dG. Total glucocorticoid receptor protein (GRt) was increased significantly by DEX at 50 and 125 dG in females only, but decreased in males at 125 dG as compared to controls. Glucocorticoid receptor α (GRα) protein was not changed after DEX treatment. Three BNC phenotypes were detected regarding GRα expression (++, +-, --), DEX increased the proportion of (++) and decreased (--) BNC at 140 dG. Effects were sex- and cell type dependent, modifying the responsiveness of the placenta to endogenous cortisol. We speculate that 3 maturational stages of BNCs exist and that the overall activity of BNCs is determined by the distribution of these 3 cell types, which may become altered through early pregnancy exposure to elevated glucocorticoids.
Topics: Animals; Caspase 3; Dexamethasone; Female; Gestational Age; Glucocorticoids; Male; Phenotype; Placenta; Placental Lactogen; Pregnancy; Protein Transport; Receptors, Glucocorticoid; Sex Factors; Sheep; Signal Transduction
PubMed: 25332218
DOI: 10.1177/1933719114553452 -
The American Journal of Case Reports Nov 2021BACKGROUND When a woman becomes pregnant, the placenta produces human placental lactogen (hPL). The anti-insulin effect of hPL raises maternal blood glucose levels,...
BACKGROUND When a woman becomes pregnant, the placenta produces human placental lactogen (hPL). The anti-insulin effect of hPL raises maternal blood glucose levels, allowing the fetus to use glucose as a nutrient. Because hPL is produced by the placenta until delivery, insulin requirements in patients with gestational diabetes mellitus (GDM) typically increase, but in some cases, they may decrease. We retrospectively examined data from women with GDM who received insulin and delivered at our hospital. CASE REPORT From April 2019 to March 2020, we targeted patients who were diagnosed with GDM, received insulin, and delivered at our hospital. GDM was diagnosed based on the guidelines from the Japanese Society of Obstetrics and Gynecology. The rate of change in insulin dosage was calculated as: (insulin dosage at delivery - insulin dosage 14 days before delivery) divided by 14. Two patients whose insulin dosage was significantly reduced developed a syndrome of hemolysis, elevated liver enzymes, and low platelet count or acute fatty liver of pregnancy and underwent emergency cesarean section. CONCLUSIONS The present case report suggests that a decrease in insulin requirement in pregnant patients with GDM can predict maternal abnormalities due to placental dysfunction.
Topics: Blood Glucose; Cesarean Section; Diabetes, Gestational; Female; Hemolysis; Humans; Insulin; Liver; Placenta; Platelet Count; Pregnancy; Retrospective Studies
PubMed: 34744160
DOI: 10.12659/AJCR.933460