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Rune Ehrenreich Kuhre, Nicolai Jacob Wewer Albrechtsen, Carolyn Fiona Deacon, Emilie Balk-Møller, Jens Frederik Rehfeld, Frank Reimann, Fiona Mary Gribble and Jens Juul Holst

Abstract

GLUTag, NCI-H716, and STC-1 are cell lines that are widely used to study mechanisms underlying secretion of glucagon-like peptide-1 (GLP-1), but the extent to which they resemble native L-cells is unknown. We used validated immunoassays for 14 different hormones to analyze peptide content (lysis samples; n = 9 from different passage numbers) or peptide secretion in response to buffer (baseline), and after stimulation with 50 mM KCl or 10 mM glucose + 10 µM forskolin/3-isobutyl-1-methylxanthine (n = 6 also different passage numbers). All cell lines produced and processed proglucagon into GLP-1, GLP-2, glicentin, and oxyntomodulin in a pattern (prohormone convertase (PC)1/3 dependent) similar to that described for human gut. All three cell lines showed basal secretion of GLP-1 and GLP-2, which increased after stimulation. In contrast to freshly isolated murine L-cells, all cell lines also expressed PC2 and secreted large amounts of pancreatic glucagon. Neurotensin and somatostatin storage was low and secretion was not consistently increased by stimulation. STC-1 cells released more glucose-dependent insulinotropic polypeptide than GLP-1 at baseline (P < 0.01) and KCl elevated its secretion (P < 0.05). Peptide YY, which normally co-localizes with GLP-1 in distal L-cells, was not detected in any of the cell lines. GLUTag and STC-1 cells also expressed vasoactive intestinal peptide, but none expressed pancreatic polypeptide or insulin. GLUTag contained and secreted large amounts of CCK, while NCI-H716 did not store this peptide and STC-1 contained low amounts. Our results show that hormone production in cell line models of the L-cell has limited similarity to the natural L-cells.

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Bolander FF Jr

In a previous study, the envelope protein (gp52) of the mouse mammary tumour virus (MMTV) was shown to facilitate mammary gland differentiation by increasing prolactin (PRL) receptors via increased receptor synthesis and via the redistribution of existing receptors from an internal pool. In this study, receptors for other hormones known to affect mammary gland metabolism were investigated. Epidermal growth factor (EGF) stimulates mammary epithelial growth and inhibits differentiation; its receptor is rapidly and dramatically down-regulated by gp52. This is accomplished by its internalization and by decreasing its half-life from 27 h to 2.4 h. Surprisingly, it also increased EGF receptor synthesis, although this effect was not great enough to overcome receptor down-regulation. In contrast, gp52 did not affect the distribution, half-life or synthesis of the insulin receptor. These results demonstrate that MMTV can enhance mammary differentiation by coordinately regulating several hormone receptors: specifically, it can increase the number of receptors for PRL, a differentiative hormone, while decreasing the number of receptors for EGF, a growth/anti-differentiative hormone.

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M Angervo, P Leinonen, R Koistinen, M Julkunen and M Seppälä

ABSTRACT

The growth-regulating actions of IGFs are modulated by their binding proteins (IGFBPs). The serum concentration of IGFBP-1 is down-regulated by insulin, and in-vitro studies have demonstrated that IGFBP-1 secretion from various tissues and cells can be stimulated by theophylline, forskolin, oestrogen and progesterone. We have studied the effects and mechanisms of thyroid hormone action on IGFBP-1 gene expression and secretion by human hepatoma cells in vitro.

Tri-iodothyronine dose-dependently enhanced IGFBP-1 secretion in serum-free HepG2 cell cultures after 24–48 h of exposure, as measured by a specific immunofluorometric assay. This was accompanied by an increase (+ 50%) in the amount of IGFBP-1 mRNA, which could be prevented by cycloheximide, a protein synthesis inhibitor. Cycloheximide transiently enhanced (+ 200%) the accumulation of IGFBP-1 mRNA at 3–12 h of incubation, when no effect of tri-iodothyronine was observed. It is concluded that thyroid hormone stimulates IGFBP-1 secretion slowly by enhancing IGFBP-1 gene expression by a protein mediator. The acute stimulation of IGFBP-1 gene transcription by cycloheximide associates this gene with a number of growth-related genes encoding growth- and tumour-associated peptides.

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S S Donkin, A D McNall, B S Swencki, J L Peters and T D Etherton

ABSTRACT

The present study was conducted to determine the chronic effects of porcine growth hormone administration on fatty acid synthase (FAS) mRNA abundance and gene transcription in growing rats. Growth hormone treatment increased growth rate approximately 27% (P<0·01). Porcine growth hormone decreased FAS mRNA levels by 55%. The reduction in FAS mRNA was due to a marked decrease in transcription of the FAS gene (decreased by 80%). In contrast, porcine growth hormone did not affect mRNA abundance or transcription rate of another insulin-regulated gene, phosphoenolpyruvate carboxykinase. In summary, our results have established that chronic treatment with growth hormone decreases FAS mRNA by decreasing the transcription rate of the gene. Furthermore, they suggest that the effects of growth hormone are specific and are not mediated by general changes in insulin-responsive gene expression in liver.

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Julian C Lui, Ola Nilsson and Jeffrey Baron

For most bones, elongation is driven primarily by chondrogenesis at the growth plates. This process results from chondrocyte proliferation, hypertrophy, and extracellular matrix secretion, and it is carefully orchestrated by complex networks of local paracrine factors and modulated by endocrine factors. We review here recent advances in the understanding of growth plate physiology. These advances include new approaches to study expression patterns of large numbers of genes in the growth plate, using microdissection followed by microarray. This approach has been combined with genome-wide association studies to provide insights into the regulation of the human growth plate. We also review recent studies elucidating the roles of bone morphogenetic proteins, fibroblast growth factors, C-type natriuretic peptide, and suppressor of cytokine signaling in the local regulation of growth plate chondrogenesis and longitudinal bone growth.

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Céline Callewaere, Ghazal Banisadr, William Rostène and Stéphane Mélik Parsadaniantz

Chemokines are small secreted proteins that chemoattract and activate immune and non-immune cells both in vivo and in vitro. In addition to their well-established role in the immune system, several recent reports have suggested that chemokines and their receptors may also play a role in the central nervous system (CNS). The best known central action is their ability to act as immunoinflammatory mediators. Indeed, these proteins regulate leukocyte infiltration in the brain during inflammatory and infectious diseases. However, we and others recently demonstrated that they are expressed not only in neuroinflammatory conditions, but also constitutively by different cell types including neurons in the normal brain, suggesting that they may act as modulators of neuronal functions. The goal of this review is to highlight the role of chemokines in the control of neuroendocrine functions. First, we will focus on the expression of chemokines and their receptors in the CNS, with the main spotlight on the neuronal expression in the hypothalamo–pituitary system. Secondly, we will discuss the role – we can now suspect – of chemokines and their receptors in the regulation of neuroendocrine functions. In conclusion, we propose that chemokines can be added to the well-described neuroendocrine regulatory mechanisms, providing an additional fine modulatory tuning system in physiological conditions.

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B C J Dirven, J R Homberg, T Kozicz and M J A G Henckens

The hypothalamic–pituitary–adrenal (HPA) axis is critically involved in the neuroendocrine regulation of stress adaptation, and the restoration of homeostasis following stress exposure. Dysregulation of this axis is associated with stress-related pathologies like major depressive disorder, post-traumatic stress disorder, panic disorder and chronic anxiety. It has long been understood that stress during early life can have a significant lasting influence on the development of the neuroendocrine system and its neural regulators, partially by modifying epigenetic regulation of gene expression, with implications for health and well-being in later life. Evidence is accumulating that epigenetic plasticity also extends to adulthood, proposing it as a mechanism by which psychological trauma later in life can long-lastingly affect HPA axis function, brain plasticity, neuronal function and behavioural adaptation to neuropsychological stress. Further corroborating this claim is the phenomenon that these epigenetic changes correlate with the behavioural consequences of trauma exposure. Thereby, epigenetic modifications provide a putative molecular mechanism by which the behavioural phenotype and transcriptional/translational potential of genes involved in HPA axis regulation can change drastically in response to environmental challenges, and appear an important target for treatment of stress-related disorders. However, improved insight is required to increase their therapeutic (drug) potential. Here, we provide an overview of the growing body of literature describing the epigenetic modulation of the (primarily neuroendocrine) stress response as a consequence of adult life stress and interpret the implications for, and the challenges involved in applying this knowledge to, the identification and treatment of stress-related psychiatric disorders.

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F Lü, K Yang, V K M Han and J R G Challis

ABSTRACT

Activation of the fetal pituitary-adrenal axis is crucial for fetal organ maturation and the onset of parturition in sheep. Many factors including corticotrophin-releasing hormone (CRH) and arginine vasopressin secreted from the hypothalamus, and growth factors produced within the pituitary may be involved in the regulation of maturation of the fetal pituitary gland. IGFs have mitogenic and differentiation-promoting capacities in a variety of organs and are synthesized as paracrine factors within developing tissues. However, there is little information concerning the synthesis, distribution, regulation and function of IGFs in the fetal pituitary gland at different times during pregnancy. Therefore, we have localized IGF-I and IGF-II mRNAs and peptides, and determined the effect of cortisol on the level of IGF-II mRNAs in the pituitary glands of developing sheep fetuses. We examined the possible effects of IGFs on corticotroph function in cultures of adenohypophysial cells from term fetuses.

Seven species of IGF-II transcripts of 1·2–6·0 kb were identified by Northern blot analysis in the pituitary gland of fetuses between day 60 of gestation and term (day 145). The levels of IGF-II mRNAs did not change significantly during pregnancy, although there was a trend for the presence of higher levels of IGF-II mRNAs at day 60 of gestation. IGF-I mRNA was not detectable. By in situ hybridization, IGF-II mRNA was localized to non-endocrine cells and to cells lining the blood vessels of the pars distalis, to some presumed endocrine cells in the pars distalis and pars intermedia, and to clusters of cells in the pars nervosa. In contrast, IGF-I and IGF-II peptides were detected in the presumed endocrine cells in the pars distalis and pars intermedia but not in the pars nervosa. Incubation of adenohypophysial cells from term fetuses with IGF-I, but not IGF-II, for 48 h increased specific 125I-Tyr-ovine CRH binding. However, neither IGF-I nor IGF-II had any significant effects on the basal or CRH-stimulated immunoreactive (ir)-ACTH output, the level of POMC mRNA or the number of ir-ACTH positive cells. Infusion of cortisol to fetuses starting at day 96 of gestation for 100 h or at days 120–125 of gestation for 84 h did not affect the level of IGF-II mRNAs in the pars distalis but decreased the levels of POMC mRNA.

These results are consistent with IGFs having the potential to influence fetal pituitary function, although probably on cell types other than the corticotrophs. The likely sources of IGFs may be predominantly local (IGF-II) or from extrapituitary sources (IGF-I).

Free access

Amy L Filby, Karen L Thorpe and Charles R Tyler

Complex interrelationships in the signalling of oestrogenic effects mean that environmental oestrogens present in the aquatic environment have the potential to disrupt physiological function in fish in a more complex manner than portrayed in the present literature. Taking a broader approach to investigate the possible effect pathways and the likely consequences of environmental oestrogen exposure in fish, the effects of 17β-oestradiol (E2) were studied on the expression of a suite of genes which interact to mediate growth, development and thyroid and interrenal function (growth hormone GH (gh), GH receptor (ghr ), insulin-like growth factor (IGF-I) (igf1), IGF-I receptor (igf1r ), thyroid hormone receptors-α (thra) and -β (thrb) and glucocorticoid receptor (gr )) together with the expression analyses of sex-steroid receptors and ten other genes centrally involved in sexual development and reproduction in fathead minnow (fhm; Pimephales promelas). Exposure of adult fhm to 35 ng E2/l for 14 days induced classic oestrogen biomarker responses (hepatic oestrogen receptor 1 and plasma vitellogenin), and impacted on the reproductive axis, feminising ‘male’ steroidogenic enzyme expression profiles and suppressing genes involved in testis differentiation. However, E2 also triggered a cascade of responses for gh, ghr, igf1, igf1r, thra, thrb and gr in the pituitary, brain, liver, gonad and gill, with potential consequences for the functioning of many physiological processes, not just reproduction. Molecular responses to E2 were complex, with most genes showing differential responses between tissues and sexes. For example, igf1 expression increased in brain but decreased in gill on exposure to E2, and responded in an opposite way in males compared with females in liver, gonad and pituitary. These findings demonstrate the importance of developing a deeper understanding of the endocrine interactions for unravelling the mechanisms of environmental oestrogen action and predicting the likely health consequences.

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G D Jahnke, C S Trempus, F W Kari and R P DiAugustine

ABSTRACT

Prolactin is a member of the growth hormone family and is required for the growth and terminal differentiation of the mammary gland. Ectopic production of this hormone has been reported in several species, including rat, sheep, goat and human mammary tissues. In this study, mouse mammary cell lines, xenographs in the mammary gland from these cell lines and from hyperplastic alveolar nodules, spontaneous tumors, and normal tissues were studied for de novo production of this growth factor. Prolactin transcripts were found by reverse transcriptase PCR in some neoplastic and preneoplastic tissues and in mouse mammary cell lines, NOG8 and CDNR4, but were not detected in the normal mouse mammary gland. Northern analysis revealed a 1 kb transcript for both cell lines that co-migrated with the prolactin pituitary transcript. Conditioned medium from NOG8 cells was positive for prolactin bioactivity by the Nb2 rat lymphoma cell proliferation assay, and Western analysis revealed the presence of immunoreactive proteins at M r 14 000 and 60 000. Prolactin-like bioactivity was not detected in conditioned medium from CDNR4 cells, but an immunoreactive protein of M r 60 000 was detected by Western analysis. The mouse mammary cell line, Comma D, was negative for prolactin transcripts; however, adenocarcinomas derived from inoculation of Comma D cells into the cleared mammary fat pad were positive by reverse transcriptase PCR in two of four cases. Hyperplastic outgrowths maintained in the cleared mammary fat pad as well as spontaneous tumors were positive for prolactin transcripts in one of four cases. These results suggest that prolactin can be produced ectopically by the neoplastic mouse mammary gland.