bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Metabolic Phenotype of Prader-Willi Syndrome (PWS) in Childhood: Heightened Insulin Sensitivity Relative to Body Mass Index
Authors: Haqq Andrea M. , Muehlbauer Michael J. , Newgard Christopher B. , Grambow Steven , Freemark Michael 
Published: January 2014

Context
Insulin sensitivity is higher in patients with Prader-Willi syndrome (PWS) than in body mass index-matched obese controls (OCs). Factors contributing to the heightened insulin sensitivity of PWS remain obscure. We compared the fasting levels of various hormones, cytokines, lipids, and liver function tests in 14 PWS patients and 14 OCs with those in 14 age- and gender-matched lean children (LC). We hypothesized that metabolic profiles of children with PWS are comparable with those of LC but different from those of OCs.

Results
Leptin levels were comparable in PWS patients and OCs, suggesting comparable degrees of adiposity. Glucose levels were comparable among groups. However, fasting insulin concentrations and homeostasis model assessment insulin resistance index were lower in PWS patients than in OCs (P &lt; 0.05) and similar to LC. Moreover, high-density lipoprotein levels were lower and triglycerides higher in OCs (P &lt; 0.05) but not PWS patients. Total adiponectin, high-molecular-weight (HMW) adiponectin and the HMW to total adiponectin ratio were higher in PWS patients (P &lt; 0.05) than in OCs and similar to LC. High-sensitivity C-reactive protein and IL-6 levels were higher in OCs than in PWS patients or LC (P &lt; 0.05). Nevertheless, PAI-1 levels were elevated in both OC and PWS patients. There were no group differences in glucagon-like peptide-1-(7-36)-amide, macrophage chemoattractant protein-1, TNFα, IL-2, IL-8, IL-10, IL-12p40, IL-18, resistin, total or low-density lipoprotein cholesterol, aspartate aminotransferase, or aminotransferase.

Conclusions
The heightened insulin sensitivity of PWS patients relative to OCs is associated with higher levels of adiponectin and lower levels of high-sensitivity C-reactive protein and IL-6. Future studies will determine whether PWS children are protected from obesity comorbidities such as type 2 diabetes, hyperlipidemia, and nonalcoholic fatty liver disease.
Dynamic Chromatin Modifications Control GnRH Gene Expression during Neuronal Differentiation and Protein Kinase C Signal Transduction
Authors: Iyer Anita K. , Brayman Melissa J. , Mellon Pamela L. 
Published: January 2014

Abstract
GnRH, a neuropeptide produced by rare, specialized hypothalamic secretory neurons, is critical for reproduction. During development, GnRH gene expression increases as neurons migrate from the olfactory placode to the hypothalamus, with highest levels in the mature, postmitotic state. While neuronal differentiation is known to be controlled by chromatin modulations, the role of chromatin dynamics in GnRH gene regulation has not been studied. Here, we use mature and immature GnRH neuronal cell models to show that both neuron-specific and protein kinase C regulation of GnRH expression are mediated by chromatin structure and histone modifications. Only in GT1-7 mature GnRH neuronal cells did GnRH regulatory elements display high sensitivity to DNase and enrichment of active histone markers histone-H3 acetylation and H3 lysine 4 trimethylation (H3K4-Me3), as well as RNA Polymerase II (RNAPII) binding and enhancer RNA transcription. In contrast, H3K9-Me2, a marker of inactive chromatin, was highest in nonneuronal cells, low in GT1-7 cells, and intermediate in immature GnRH neuronal cells. The chromatin of the GnRH gene was therefore active in mature GnRH neuronal cells, inactive in nonneuronal cells, but not fully inactive in immature GnRH neuronal cells. Activation of protein kinase C (PKC) potently represses GnRH expression. PKC activation caused closing of the chromatin and decreased RNAPII occupancy at the GnRH minimal promoter (−278/−97). At GnRH-Enhancer-1 (−2404/−2100), PKC activation decreased phosphorylated-RNAPII binding, enhancer RNA transcription, and H3 acetylation, and reciprocally increased H3K9-Me2. Chromatin modifications therefore participate in the dynamic regulation and specification of GnRH expression to differentiated hypothalamic neurons.
Progesterone Regulates Osteopontin Expression in Human Trophoblasts: A Model of Paracrine Control in the Placenta?*
Authors: Omigbodun Akinyinka , Ziolkiewicz Piotr , Tessler Cheryl , Hoyer John R. , Coutifaris Christos 
Published: January 2014

AbstractOsteopontin (OPN), a matrix glycosylated phosphoprotein, has been proposed to play a role(s) in basic cellular processes, such as neovascularization and tissue remodeling, which are essential to placental morphogenesis and embryo implantation. We have shown OPN to be expressed by cytotrophoblasts of the chorionic villus, and a putative progesterone regulatory element in the OPN promoter suggests hormonal regulatory control. This led us to test the hypothesis that progesterone regulates OPN expression in human cytotrophoblasts. Cytotrophoblasts isolated from human placentas were treated with combinations of progesterone, RU486, and/or aminoglutethimide, and their expression of OPN was assessed by Northern hybridization and immunocytochemistry. The expression of OPN messenger RNA (mRNA) declined as trophoblasts aggregated, but rebounded at later times when syncytia and mononuclear cytotrophoblasts coexisted in culture. Progesterone increased OPN mRNA expression by aggregating mononuclear cytotrophoblasts. Aminoglutethimide suppression of endogenous steroidogenesis by syncytiotrophoblasts inhibited OPN expression, whereas the addition of exogenous progesterone to cells treated with aminoglutethimide reversed this inhibitory effect. These observations were confirmed at the protein level by immunocytochemistry. Treatment of cytotrophoblasts with both progesterone and RU486 inhibited the up-regulatory effect on OPN mRNA associated with exposure to progesterone alone, further confirming a direct effect of progesterone. We conclude that progesterone up-regulates OPN expression in human cytotrophoblasts, and we propose that in vivo, progesterone secretion by syncytiotrophoblasts regulates the expression of OPN by the underlying cytotrophoblasts. As the receptors for OPN,α v integrins, are expressed by syncytiotrophoblasts, we postulate that these paracrine regulatory mechanisms contribute to the adhesive and/or signaling events between the two trophoblast cell types of the chorionic villus.
Transforming Growth Factor-β1 Inhibits Membrane Association of Protein Kinase Cα in a Human Prostate Cancer Cell Line, PC3*
Authors: Lamm Marilyn L. G. , Long Denise D. , Goodwin Shannon M. , Lee Chung 
Published: January 2014

AbstractThe postreceptor signaling pathway(s) that mediates the effects of transforming growth factor-β1 (TGF-β1) is incompletely understood. The present study investigated the involvement of protein kinase C (PKC) in the growth-inhibitory action of TGF-β1 in PC3, a human prostate cancer cell line. PKCα, the only conventional PKC isoform detected in PC3 cells, appeared to be constitutively active based on its presence in both Triton-soluble membrane fraction and cytosol. However, levels of membrane-associated PKCα were decreased by a growth-inhibitory dose of TGF-β1. The response to TGF-β1 was rapid (within 5 min), time dependent, isoform specific, and occurred without apparent changes in levels of total PKCα protein. TGF-β1 also decreased the levels of membrane-associated PKC activity coincident with its inhibitory effect on PKCα’s membrane association. Inhibition of PKC activity appeared to be associated with growth inhibition in PC3 cells, because chelerythrine (a specific PKC inhibitor) likewise decreased cell proliferation. Taken together, our data suggest that inhibition of PKC activity, at least in part due to inactivation of PKCα, is an early event associated with TGF-β1 postreceptor signaling that might mediate suppression of cell proliferation.
Estradiol Requirements for Induction and Maintenance of the Gonadotropin-Releasing Hormone Surge: Implications for Neuroendocrine Processing of the Estradiol Signal*
Authors: Evans N. P. , Dahl G. E. , Padmanabhan V. , Thrun L. A. , Karsch F. J. 
Published: January 2014

Abstract
Two experiments were performed to examine the temporal requirements of the estradiol signal for the GnRH and LH surges in the ewe. Hypophyseal portal and jugular blood (to measure GnRH and LH, respectively) were sampled from ewes set up in an artificial follicular phase model. After progesterone withdrawal to simulate luteolysis, circulating estradiol was raised to a preovulatory level by inserting estradiol implants, which then were removed at different times to vary estradiol signal duration. The objective of the first experiment was to assess the effect of withdrawing estradiol at surge onset on development and maintenance of the GnRH/LH surges. Removal of estradiol, before surge onset, neither altered the LH surge in relation to that induced when the estradiol stimulus was maintained nor affected stimulation of a massive and sustained GnRH surge that outlasted the LH surge by many hours. Continued estradiol treatment, however, did prolong the GnRH surge. In the second experiment, the estradiol stimulus was shortened to test the hypothesis that estradiol need not be present for the whole presurge period to induce GnRH/LH surges. Ewes received estradiol either up to the time of surge onset (21 h) or for periods equivalent to the last 14 h, the last 7 h, or the earliest 7 h of the 21-h signal. Shortening the signal to 14 h did not reduce its ability to stimulate a full GnRH surge, but it did reduce the amplitude of the resultant LH surge. Further shortening of the signal to 7 h, however, produced a mixed response. Most animals (8 of 10 combining the two 7-h groups) did not express GnRH surges. In the two ewes that did, GnRH surge amplitude and duration were again within the range observed with the 21-h estradiol signal, but the LH response was greatly reduced.
These results indicate that, once the GnRH/LH surges of the ewe have begun, elevated estradiol is not required for surge maintenance. Development of a full GnRH surge requires elevated estradiol for only a portion of the presurge period. More prolonged exposure to estradiol, however, is needed to maximize pituitary responsiveness to GnRH. Since the estradiol signal for the GnRH surge is relatively short (7–14 h) and temporally located well in advance of the surge itself, these results are consistent with the hypothesis that estradiol is required only to activate the steroid-responsive neuronal elements and not for progression of the signal from these elements to the actual surge process of GnRH release.
Maternal Nonthyroidal Illness and Fetal Thyroid Hormone Status, as Studied in the Streptozotocin-Induced Diabetes Mellitus Rat Model*
Authors: Calvo Rosa , Morreale de Escobar Gabriella , Escobar del Rey Francisco , Obregón Maria-Jesús 
Published: January 2014

Abstract
We have used the streptozotocin-induced diabetes mellitus pregnant rat as a model of maternal nonthyroidal illness. We measured the effects of different degrees of diabetes mellitus on maternal body weight, the outcome of pregnancy, circulating glucose, insulin, T4, T3, rT3, and TSH in mother and fetus, T4 and T3 in maternal and fetal tissues, and iodothyronine deiodinases in liver, lung, and brain.
All of the changes in thyroid hormone status typical of nonthyroidal illnesses were observed in the mothers and were related to the degree of the metabolic imbalances. Most were controlled with a daily insulin dose of 0.5 U/100 g BW. Normalization of maternal placental T4, however, required higher insulin doses than in other maternal tissues.
The number and body weight of the fetuses, their pituitary GH contents, and their thyroid hormone status were severely affected. The total extrathyroidal T4 and T3 pools decreased to one third of normal fetal values. T4 and T3 concentrations in the fetal brain were lower than normal, and the expected increase in type II 5′deiodinase activity was not observed. The low cerebral T3 only improved with adequate insulin treatment of the dams.
It is concluded that maternal diabetes mellitus, and possibly other nonthyroidal illnesses that impair the availability of intracellular energy stores, may affect fetal brain T3 when thyroid hormones are essential for normal development.
Retinoic Acids Increase 17β-Hydroxysteroid Dehydrogenase Type 1 Expression in JEG-3 and T47D Cells, but the Stimulation Is Potentiated by Epidermal Growth Factor, 12-O-Tetradecanoylphorbol-13-Acetate, and Cyclic Adenosine 3′,5′-Monophosphate Only in JEG-3 Cells*
Authors: Piao Yun-shang , Peltoketo Hellevi , Jouppila Annukka , Vihko Reijo 
Published: January 2014

AbstractHuman 17β-hydroxysteroid dehydrogenase type 1 (17HSD type 1) primarily catalyzes the reduction of low activity estrone to high activity estradiol in ovarian granulosa cells and placental trophoblasts. 17HSD type 1 is also present in certain peripheral tissues, such as breast tissue. In the present study we investigated the effects of retinoic acids (RAs) together with other stimuli known to modulate estradiol production and/or cell growth on expression of 17HSD type 1 in JEG-3 choriocarcinoma cells and estrogen-responsive T47D breast cancer cells. Treatment of cultured JEG-3 and T47D cells with all-trans-RA and 9-cis-RA increased reductive 17HSD activity and 17HSD type 1 messenger RNA expression severalfold in both cell lines. On the other hand, epidermal growth factor (EGF), Ca ionophore, the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA), and cAMP elevated 17HSD type 1 expression only in JEG-3 cells. Correspondingly, the effects of RAs were potentiated by EGF, TPA, and cAMP in JEG-3 cells, whereas no such phenomenon was observed in T47D cells. In JEG-3 cells, simultaneous administration of RAs with TPA and EGF maximally resulted in approximately 40- and 20-fold increases in 17HSD type 1 messenger RNA expression, respectively. The present data indicate that RAs may stimulate estradiol biosynthesis by regulating 17HSD type 1 expression in certain breast cancer and choriocarcinoma cells. The results suggest that interaction of multiple regulatory pathways is involved in maintaining high 17HSD type 1 expression in the placenta. In addition, regulation of 17HSD type 1 expression may be different in trophoblast cells from that in breast epithelial cells.
Adrenocorticotropin Response and Nicotine-Induced Norepinephrine Secretion in the Rat Paraventricular Nucleus Are Mediated through Brainstem Receptors*
Authors: Fu Yitong , Matta Shannon G. , Valentine James D. , Sharp Burt M. 
Published: January 2014

Abstract
Nicotine is a potent stimulus for the secretion of ACTH, and norepinephrinergic neurons originating in the brainstem are involved. Prior reports using in vivo microdialysis in alert rats have shown that nicotine, administered ip or into the fourth ventricle, stimulated the release of norepinephrine (NE) into the hypothalamic paraventricular nucleus (PVN), the site of neurons containing CRH. In the present studies, rats received an iv infusion of nicotine into the jugular vein on alternate days during their active (dark) phase; therefore, direct correlations between the levels of NE microdialyzed from the PVN and plasma ACTH could be made in each animal. Nicotine administered iv (0.045–0.135 mg/kg) elicited dose-dependent increases in both NE and ACTH (P &lt; 0.01). A significant correlation was found between nicotine-stimulated NE release in the PVN and ACTH secretion (r = 0.91, P &lt; 0.01). To address whether the site(s) of action of nicotine was on presynaptic receptors on NE terminals in the PVN or on receptors on neurons in brainstem regions accessible from the fourth ventricle, the nicotinic cholinergic antagonist, mecamylamine (0.1–4.8 μg), was microinjected directly into the PVN or into the fourth ventricle before nicotine infusion. Fourth-ventricular administration of mecamylamine (1.6 μg) or higher, before iv nicotine (0.09 mg/kg), completely blocked both NE release in the PVN (IC50 = 0.64 μg) and ACTH secretion (IC50 = 0.40 μg) (P &lt; 0.01, compared with vehicle before nicotine), whereas it was ineffective when injected directly into the PVN. The results demonstrate that the nicotinic cholinergic receptors in the brainstem, rather than presynaptic receptors within the PVN itself, mediate nicotine-stimulated PVN NE release and ACTH secretion.
Contrasted Impact of Maternal Rat Food Restriction on the Fetal Endocrine Pancreas*
Authors: Alvarez C. , Martín M. A. , Goya L. , Bertin E. , Portha B. , Pascual-Leone A. M. 
Published: January 2014

Abstract
The effects of food restriction of the mother (65% restriction of ad libitum food intake) on fetal and maternal insulin secretion and islet function were studied at 21 days gestation in three different rat populations: 1) undernourished from 0–7 days gestation, 2) undernourished from 7–14 days gestation, and 3) undernourished from 14–21 days gestation. The body weights of mothers were decreased in groups 2 and 3 vs. those in control fed pregnant animals, and no changes in basal parameters were found in any group. A glucose tolerance test in mothers from group 3 showed a mild intolerance to glucose and a decreased islet insulin content, although islet stimulation in vitro with glucose alone or plus arginine showed a normal insulin secretory response. Body weight was decreased in fetuses from the three groups (P &lt; 0.01), and pancreas weight was reduced only in group 3. Insulinemia was increased in groups 2 and 3, and pancreatic insulin content increased only in group 3. However, fetuses from mothers of group 3 showed increased islet insulin content, increased response of insulin in vitro to glucose or glucose plus arginine, and hypertrophy of β-cell mass. These results indicate, first, that the development of the fetal pancreas depends on a balanced maternal glucose homeostasis and, second, that adaptive maternal changes to undernutrition seem to induce alterations on the fetal endocrine pancreas, especially when food restriction is applied during the last week of gestation.
Leptin Signaling in the Hypothalamus of Normal Rats in Vivo**This work was supported in part by a Boston Obesity Nutrition Research Center Grant (to J.C.C.), NIH Grant DK-50411 (to R.J.S.), and NIH Diabetes and Endocrinology Center Grant DK-36836 (to R.J.S.).
Authors: McCowen Karen C. , Chow Jesse C. , Smith Robert J. 
Published: January 2014

Abstract
Leptin has been shown to activate multiple signaling molecules in cultured cells, including Janus kinase-2, STAT (signal transducer and activator of transcription) proteins, and mitogen-activated protein kinase, and to stimulate the DNA-binding activity of STAT3 in mouse hypothalamus. In this study, the activation of candidate leptin signaling molecules in the hypothalamus of normal rats in vivo was investigated. Fasted male Sprague-Dawley rats were injected iv with recombinant murine leptin or vehicle. Plasma leptin concentrations were determined at defined time points, and the phosphorylation of signaling proteins was assessed in hypothalamic lysates. There was a marked increase in plasma leptin concentration at 2 min and a gradual decline by 45 min after leptin injection. Immunoblotting analysis of hypothalamic lysates with a phosphospecific STAT3 antibody demonstrated a time-dependent stimulation of STAT3 tyrosine phosphorylation. STAT3 phosphorylation was first evident at 5 min and was maximal at 30 min after leptin injection. By contrast, leptin did not increase the phosphorylation of Janus kinase proteins, mitogen-activated protein kinase, or STAT1 and -5 despite abundant expression of these signaling molecules in the hypothalamus. These results differ from findings in cultured cells and in vitro systems. It remains unclear how signaling is propagated downstream from the leptin receptor to STAT3, but this may involve novel signaling intermediates.
Importance of the Gonadotropin-Releasing Hormone (GnRH) Surge for Induction of the Preovulatory Luteinizing Hormone Surge of the Ewe: Dose-Response Relationship and Excess of GnRH*
Authors: Bowen Jennifer M. , Dahl Geoffrey E. , Evans Neil P. , Thrun Lori A. , Wang Yuedong , Brown Morton B. , Karsch Fred J. 
Published: January 2014

Abstract
The preovulatory LH surge in the ewe is stimulated by a large sustained surge of GnRH. We have previously demonstrated that the duration of this GnRH signal exceeds that necessary to initiate and sustain the LH surge. The objective of the present study was to determine whether a similar excess exists for amplitude of the GnRH surge. Experiments were performed using an animal model in which GnRH secretion was blocked by progesterone, which in itself does not block the pituitary response to GnRH. To assess the amplitude of the GnRH surge needed to induce the LH surge, we introduced artificial GnRH surges of normal contour and duration but varying amplitudes. Twelve ewes were run through 3 successive artificial follicular phases (total of 36). Six of these artificial follicular phases were positive controls, in which progesterone was removed, the estradiol stimulus was provided, and vehicle was infused. In these control cycles, animals generated endogenous LH surges. In the remaining artificial follicular phases, progesterone was not withdrawn, the estradiol stimulus was provided, and either vehicle (negative control) or GnRH solutions of varying concentrations (experimental) were infused. The circulating GnRH concentrations achieved by infusion were monitored. No LH surges were observed in negative controls, whereas LH surges were induced in experimental cycles provided a sufficient dose of GnRH was infused. A highly significant dose-response relationship was observed between the amplitude of the GnRH surge and both the amplitude of the LH surge and the area under the curve describing the LH response, but no such relationship existed between the amplitude of the GnRH surge and the duration of the LH response. In numerous cases, LH surges similar to those in the positive control animals resulted from infusion of amounts of GnRH estimated to be considerably less than those delivered to the pituitary during the endogenously generated GnRH/LH surge. These findings indicate that, in the ewe, increased GnRH secretion drives the preovulatory LH surge in a dose-dependent fashion, and they provide evidence that the amplitude of the GnRH surge may exceed that needed to generate the LH surge.