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GH has previously been shown to be present in peripheral extrapituitary tIssues of chick embryos, but the cellular distribution of GH immunoreactivity is still uncertain because of differing immunohistochemical findings. The possibility that this uncertainty reflects differences in fixation of the embryonic tIssues was assessed by comparing GH immunoreactivity in tIssues fixed in 4% (w/v) paraformaldehyde or Carnoy's fluid (60% ethanol (v/v); 30% chloroform (v/v); 10% acetic acid (v/v)). A widespread distribution of GH immunoreactivity was seen in paraformaldehyde-fixed tIssues, although it was particularly intense in the spinal cord, dorsal and ventral root ganglia, notochord, myotome, epidermis, crop, heart, lung and humerus. In marked contrast, GH immunoreactivity in embryonic tIssues fixed with Carnoy's was more discrete and mainly restricted to marginal and mantle layers of the spinal cord, spinal nerves, the ventral root ganglia and the extensor nerve of the anterior limb bud. Since these are neural derivatives, Carnoy's fixation appears to preferentially result in neural GH staining, whereas GH staining in neural and non-neural tIssues is seen after paraformaldehyde fixation. Carnoy's, because it is a precipitive fixative, may only fix large GH moieties, whereas GH in peripheral tIssues includes numerous molecular variants, many of which are of relatively small size. Paraformaldehyde, because it is a cross-linking fixative, preferentially fixes peptides and small proteins, and it may therefore fix more GH moieties than Carnoy's fluid. Carnoy's fixation appears to underestimate GH immunoreactivity in immunohistochemical studies on the cellular distribution of GH-like proteins in embryonic chicks.
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ABSTRACT
Medroxyprogesterone acetate (MPA; 5 μg/g body wt) or norethisterone oenanthate (NET-OEN; 4 μg/g body wt) was given to lactating female rats by subcutaneous injection 1 day after parturition. Each female suckled ten female pups which had been randomly allocated to her and at 21 days of age the pups were weaned. In this way female pups were exposed to either MPA or NET-OEN via milk during suckling. The patterns of LH and progesterone secretion at pro-oestrus were investigated using radioimmunoassay. When these pups reached adulthood it was found that neonatal exposure to MPA via milk significantly reduced the pro-oestrous LH peak by 45% as well as the total amount (by 27%) of LH secreted during pro-oestrus. Neonatal exposure via milk to NET-OEN had no effect on LH secretion during pro-oestrus. Pro-oestrous progesterone secretion was unaffected by either MPA or NET-OEN treatment.
J. Endocr. (1984) 100, 149–154
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Search for other papers by S. SALISBURY MURPHY in
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SUMMARY
The coated charcoal immunoassay method was applied to the measurement of the corticotrophin (ACTH) response to insulin hypoglycaemia, lysine-vasopressin, metyrapone and surgical stress in female piglets. The maximum ACTH responses average 392 picograms (pg.)/ml. (insulin hypoglycaemia), 111 pg./ml. (lysine-vasopressin) and exceeded 350 pg./ml. after metyrapone. The time relationships between blood sugar, 11-hydroxycorticosteroid and ACTH levels were also examined. Despite constant infusion rates, the ACTH response to lysine-vasopressin was not sustained. Previous administration of dexamethasone suppressed the response to insulin hypoglycaemia and lysine-vasopressin.
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Search for other papers by Kevin G Murphy in
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Search for other papers by Steve Bloom in
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The next 60 years promise to arouse the interest of scientists and clinicians while challenging the central dogmas of endocrine physiology. In this review we consider the fundamental changes in the understanding of endocrine physiology that have taken place in recent years and the new hormones discovered. We discuss how the brain is emerging as an important regulator of endocrine and neuroendocrine circuits. Advances in molecular biology techniques and the use of genomics and other -omics in furthering our understanding of endocrine physiology are also discussed. Finally, we propose that in 2066 we may prescribe designer hormones to healthy subjects.
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Search for other papers by SR Bloom in
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Orexin-A and orexin-B (the hypocretins) are recently described neuropeptides suggested to have a physiological role in the regulation of food intake in the rat. We compared the orexigenic effect of the orexins administered intracerebroventricular (ICV) with other known stimulants of food intake, one strong, neuropeptide Y (NPY), and two weaker, melanin-concentrating hormone (MCH) and galanin. Orexin-A consistently stimulated food intake, but orexin-B only on occasions. Both peptides stimulated food intake significantly less than NPY, but to a similar extent to MCH (2 h food intake: NPY 3 nmol, 7.2+/-0.9 g vs saline, 1.5+/-0.2 g, P<0.001, MCH 3 nmol, 3.2+/-0.8 g vs saline, P<0.01, orexin-B 30 nmol, 2. 6+/-0.5 g vs saline, P=0.11) and to galanin (1 h food intake: galanin 3 nmol, 2.0+/-0.4 g vs saline, 0.8+/-0.2 g, P<0.05, orexin-A 3 nmol 2.2+/-0.4 g vs saline, P<0.01; 2 hour food intake: orexin-B 3 nmol, 2.4+/-0.3 g vs saline, 1.3+/-0.2 g, P<0.05). Following ICV orexin-A, hypothalamic c-fos, a maker of neuronal activation, was highly expressed in the paraventricular nucleus (PVN), and the arcuate nucleus (P<0.005 for both). IntraPVN injection of orexin-A stimulated 2 h food intake by one gram (orexin-A 0.03 nmol, 1.6+/-0. 3 g vs saline, 0.5+/-0.3 g, P<0.005). These findings support the suggestion that the orexins stimulate food intake. However, this effect is weak and may cast doubt upon their physiological importance in appetite regulation in the rat.
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Relaxin-3 is a member of the insulin superfamily. It is expressed in the nucleus incertus of the brainstem, which has projections to the hypothalamus. Relaxin-3 binds with high affinity to RXFP1 and RXFP3. RXFP3 is expressed within the hypothalamic paraventricular nucleus (PVN), an area central to the stress response. The physiological function of relaxin-3 is unknown but previous work suggests a role in appetite control, stimulation of the hypothalamic–pituitary–gonadal axis and stress. Central administration of relaxin-3 induces c-fos expression in the PVN and increases plasma ACTH levels in rats. The aim of this study was to investigate the effect of central administration of human relaxin-3 (H3) on the hypothalamic–pituitary–adrenal (HPA) axis in male rodents in vivo and in vitro. Intracerebroventricular (i.c.v) administration of H3 (5 nmol) significantly increased plasma corticosterone at 30 min following injection compared with vehicle. Intra-PVN administration of H3 (1.8–1620 pmol) significantly increased plasma ACTH at 1620 pmol H3 and corticosterone at 180–1620 pmol H3 at 30 min following injection compared with vehicle. The stress hormone prolactin was also significantly raised at 15 min post-injection compared with vehicle. Treatment of hypothalamic explants with H3 (10–1000 nM) stimulated the release of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP), but H3 had no effect on the release of ACTH from in vitro pituitary fragments. These results suggest that relaxin-3 may regulate the HPA axis, via hypothalamic CRH and AVP neurons. Relaxin-3 may act as a central signal linking nutritional status, reproductive function and stress.
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Abstract
The secretion of peptide 23 by rat pituitary cells is stimulated by growth hormone-releasing hormone and inhibited by somatostatin. Recent cloning of the cognate cDNA for peptide 23 revealed that it is identical to pancreatitis-associated protein (PAP). In the present study, the clearance and tissue uptake of recombinant peptide 23/PAP in normal adult male rats was assessed. The plasma half-life of recombinant peptide 23/PAP was 4·8 ±1·4 (s.d.) min. Maximal accumulation of radiolabelled peptide 23/PAP was observed in the kidney, stomach, small intestine and pancreas whereas negligible uptake was seen in the liver, lung or heart. Peptide 23/PAP was detected in a variety of tissue extracts using a radioimmunoassay. Extracts of ileum contained the highest concentrations of peptide 23/PAP. In situ hybridization analysis showed that peptide 23/PAP mRNA was highly expressed in the columnar epithelial cells of ileum, jejunum and duodenum. These observations demonstrate that peptide 23/PAP, a protein previously thought to be of pituitary origin, is widely expressed in the gastrointestinal tract and that it is rapidly removed from the circulation by the kidney and by tissues which express peptide 23/PAP.
Journal of Endocrinology (1995) 145, 461–469
Biomedical Research Group, UCD School of Biomolecular and Biomedical Sciences, School of Biomedical Sciences, School of Physical Education, Department of Science, Institute of Technology Tallaght, Dublin, Ireland
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In this work, our aim was to determine whether l-arginine (a known insulinotropic amino acid) can promote a shift of β-cell intermediary metabolism favoring glutathione (GSH) and glutathione disulfide (GSSG) antioxidant responses, stimulus–secretion coupling and functional integrity. Clonal BRIN-BD11 β-cells and mouse islets were cultured for 24 h at various l-arginine concentrations (0–1.15 mmol/l) in the absence or presence of a proinflammatory cytokine cocktail (interleukin 1β, tumour necrosis factor α and interferon γ). Cells were assessed for viability, insulin secretion, GSH, GSSG, glutamate, nitric oxide (NO), superoxide, urea, lactate and for the consumption of glucose and glutamine. Protein levels of NO synthase-2, AMP-activated protein kinase (AMPK) and the heat shock protein 72 (HSP72) were also evaluated. We found that l-arginine at 1.15 mmol/l attenuated the loss of β-cell viability observed in the presence of proinflammatory cytokines. l-Arginine increased total cellular GSH and glutamate levels but reduced the GSSG/GSH ratio and glutamate release. The amino acid stimulated glucose consumption in the presence of cytokines while also stimulating AMPK phosphorylation and HSP72 expression. Proinflammatory cytokines reduced, by at least 50%, chronic (24 h) insulin secretion, an effect partially attenuated by l-arginine. Acute insulin secretion was robustly stimulated by l-arginine but this effect was abolished in the presence of cytokines. We conclude that l-arginine can stimulate β-cell insulin secretion, antioxidant and protective responses, enabling increased functional integrity of β-cells and islets in the presence of proinflammatory cytokines. Glucose consumption and intermediary metabolism were increased by l-arginine. These results highlight the importance of l-arginine availability for β-cells during inflammatory challenge.
Department of Child Health, University of Arizona College of Medicine, Phoenix, Arizona, USA
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Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
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Traumatic brain injury (TBI) can damage the hypothalamus and cause improper activation of the growth hormone (GH) axis, leading to growth hormone deficiency (GHD). GHD is one of the most prevalent endocrinopathies following TBI in adults; however, the extent to which GHD affects juveniles remains understudied. We used postnatal day 17 rats (n = 83), which model the late infantile/toddler period, and assessed body weights, GH levels, and number of hypothalamic somatostatin neurons at acute (1, 7 days post injury (DPI)) and chronic (18, 25, 43 DPI) time points. We hypothesized that diffuse TBI would alter circulating GH levels because of damage to the hypothalamus, specifically somatostatin neurons. Data were analyzed with generalized linear and mixed effects models with fixed effects interactions between the injury and time. Despite similar growth rates over time with age, TBI rats weighed less than shams at 18 DPI (postnatal day 35; P = 0.03, standardized effect size [d] = 1.24), which is around the onset of puberty. Compared to shams, GH levels were lower in the TBI group during the acute period (P = 0.196; d = 12.3) but higher in the TBI group during the chronic period (P = 0.10; d = 52.1). Although not statistically significant, TBI-induced differences in GH had large standardized effect sizes, indicating biological significance. The mean number of hypothalamic somatostatin neurons (an inhibitor of GH) positively predicted GH levels in the hypothalamus but did not predict GH levels in the somatosensory cortex. Understanding TBI-induced alterations in the GH axis may identify therapeutic targets to improve the quality of life of pediatric survivors of TBI.
