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Deficiency in insulin secretion is a fundamental part in the pathogenesis of all forms of diabetes, determined by impaired secretory function and inadequate beta-cell mass. Growth hormone (GH) is a multifunctional hormone, involved in cellular metabolism, mitogenesis and differentiation. In pancreatic islets, GH is involved in maintaining beta-cell mass, stimulating islet hormone production and insulin secretion, and, therefore, plays a role in maintaining normal insulin sensitivity and glucose homeostasis. The intracellular events that convey the GH signal into various cellular responses remain incompletely understood. In this review, we discuss GH signaling in the beta-cells, with emphasis on Ca(2+) handling and insulin secretion regulated by human GH (hGH). hGH-stimulated rise in [Ca(2+)](i) is dependent on extracellular Ca(2+) and is mediated by Ca(2+)-induced Ca(2+) release (CICR) in the beta-cell. This process is triggered by hGH-stimulated activation of the non-receptor tyrosine kinases JAK2 and c-Src, which causes tyrosine phosphorylation of RyRs, resulting in sensitization of CICR. The rise in [Ca(2+)](i) elicited by hGH is associated with an enhanced insulin secretion, effects that are mediated mainly through the prolactin receptor. These mechanisms indicate that a rise in [Ca(2+)](i) elicited by activation of PRLR is JAK2-dependent and is associated with enhanced insulin secretion. In contrast, GH receptor-mediated increase in [Ca(2+)](i) is JAK2-independent and is dissociated from insulin secretion.
Mol Cell Endocrinol 2009 Jan 15
PMID:Growth hormone signaling in pancreatic beta-cells--calcium handling regulated by growth hormone. 1860 47

Growth hormone [GH] administration results in a reduction in adiposity of humans that is attributed to stimulation of lipolysis. We examined the effect of direct addition of human GH, in both the absence and presence of dexamethasone [Dex], as well as that of interferon beta on lipolysis by omental adipose tissue explants from obese women incubated for 48h in primary culture. There was a significant stimulation of lipolysis by GH in the presence of Dex but not by Dex or GH alone. There was also a significant further stimulation by GH in the presence of Dex of hormone-sensitive lipase, perilipin, lipoprotein lipase and beta1 adrenergic receptor mRNA. We conclude that the direct lipolytic effect of GH is accompanied by an increase in HSL mRNA in the presence of DEX, but GH also increased the mRNAs for other proteins that could explain all or part of its lipolytic action.
Mol Cell Endocrinol 2008 Nov 25
PMID:Stimulation of human omental adipose tissue lipolysis by growth hormone plus dexamethasone. 1864 Jul 75

An ontogenetic and endocrinological study has been designed on developing rats in uterus of mothers tryptophan deprived at day 1 (exp. 1) and day 14.5 (exp. 2) of conception to verify the supposed determining role of the serotoninergic system (SS) in sexual differentiation in mammals. Tryptophan-free feeding has been pursued uninterruptedly in the litter after birth, during lactation and postnatal development. Tryptophan-free pregnant rats were obtained by exclusion of tryptophan sources from chow. In both exp. 1 and exp. 2 the litter showed at birth a significant physical under evolution, that worsened, during post-natal development, to a much more marked dwarfism in exp. 1 pups. At 30 days postnatal age, whereas the female exp. 1 rats showed a right-timed onset of puberty, neither descensus of the testes nor spermatogenesis could be observed in the male rats of the same experiment. Endocrinologically the males showed a significant reduction of plasma FSH levels, but also a slight increase of those of LH. Moreover, a marked hypoandrogenism and a severe hypoprolactinemia characterized the males of this group. Hypoprolactinemia was the major endocrinological finding also in the female litter, which, however, at 30 days p.n. age showed the typical histological patterns of a cycling ovary, i.e. growing secondary follicles with scattered antral spaces, and thus a right-timed pubertal maturation, in spite of the significant lower plasma levels of pituitary gonadotropins and sex steroids. When mothers were tryptophan deprived at 14.5 of pregnancy (exp. 2), the litters showed a less marked dwarfism, persistent, severe hypoprolactinemia as in exp. 1 rats, but a normal right-timed onset of puberty in both male and female rats. Taken together these findings confirm on the one hand the close relationship between SS and PRL. On the other hand, they suggest a major, crucial role of PRL played in the male rat before day 14.5 of intrauterine development, presumably intervening in the synthesis of LH receptors sites by the maturing Leydig cells in the male gonads. Growth hormone concentrations in both sexes dwarf rats were lower than in control rats.
J Mol Histol 2008 Oct
PMID:Embryonic and postnatal development in experimental tryptophan deprived rats. A preliminary study. 1871 58

To elucidate possible mechanisms behind the endocrine control of parr-smolt transformation, the daily plasma profiles in thyroid hormones (TH; free thyroxine (FT(4)), total thyroxine (TT(4)), and total 3,5,3'-triiodothyronine (TT(3))), growth hormone (GH) and cortisol were studied in Atlantic salmon parr and smolts under simulated-natural winter (8 L:16D) and spring (16.5 L:7.5D) photoperiods, respectively. Overall, TT(4), TT(3) and GH levels were higher in smolts than in parr, whereas FT(4) levels fluctuated within the same range in parr and smolts. Significant diurnal changes in plasma TH were present in parr. Both FT(4) and TT(4) levels increased during the photophase and decreased during the scotophase, while TT(3) levels followed an inverse pattern. Growth hormone showed no significant changes in parr. Changes in FT(4), TT(4), GH, and cortisol, but not TT(3), levels, were observed in smolts with peak levels during both the photophase and scotophase for FT(4), TT(4) and GH. Plasma cortisol was not assayed in parr but in smolts the peaks were associated with dusk and dawn. In addition to the general increases in TH, GH and cortisol, the distinct endocrine differences in nighttime levels between parr in the winter and smolts in the spring suggest different interactions between TH, GH, cortisol and melatonin at these different time points. These spring scotophase endocrine profiles may represent synergistic hormone interactions that promote smolt development, similar to the synergistic endocrine interactions shown to accelerate anuran metamorphosis. The variations in these diurnal rhythms between parr and smolts may represent part of the endocrine mechanism for the translation of seasonal information during salmon smoltification.
Comp Biochem Physiol A Mol Integr Physiol 2008 Dec
PMID:Daily endocrine profiles in parr and smolt Atlantic salmon. 1879 69

Growth hormone (GH) mRNA and protein have recently been demonstrated in the rat lung throughout the period of alveolarization (day 4-14 postnatally). The functional significance of this finding was therefore assessed, by determining the effects of GH mRNA knockout using aerosolized antisense oligodeoxynucleotides (ODN) directed against the GH gene. In a preliminary experiment, the effectiveness of the antisense GH ODN was demonstrated in a lung Type II epithelial cell line (L2 cells), in which constitutive GH mRNA expression was completely abolished by GH ODN transfection. Administration of the aerosolized GH ODN to 4-day-old rats for 10 days was accompanied by a widespread presence of its delivery liposomes within lung cells. Aerosolized GH ODN treatment decreased lung concentrations of IGF (insulin-like growth factor)-1 and increased concentrations of albumin, calcyclin binding protein, superoxide dismutase, RNA binding protein motif 3, and the alpha- and beta-subunits of ATP synthase and electron transfer flavoprotein. At least 32 other proteins (identified by 2D gel electrophoresis) were also significantly affected by the antisense GH ODN treatment. By changing the lung proteome, these results indicate hitherto unsuspected autocrine/paracrine actions of GH in developmental lung function.
Mol Cell Biochem 2009 Jan
PMID:Growth hormone-dependent changes in the rat lung proteome during alveorization. 1898 81

Growth hormone (GH) is secreted in a pulsatile fashion from the pituitary gland into the circulation. Release is governed by two hypothalamic neuropeptides, growth hormone-releasing hormone (GHRH) and somatostatin (SRIF), resulting in secretion episodes with a periodicity of 3.3 h in the male rat. Ghrelin is an additional recently identified potent GH-secretagogue. However, its in vivo interactions with the GH neuroendocrine axis remain to be elucidated. Moreover, two different sites of ghrelin synthesis are involved, the stomach and the hypothalamus. We used our previously developed core model of GH oscillations and added the sites of ghrelin action at the pituitary and in the hypothalamus. With this extended model, we simulated the effects of central and peripheral ghrelin injections, monitored the GH profile and compared it with existing experimental results. Systemically administered ghrelin elicits a GH pulse independent of SRIF, but only in the presence of GHRH. The peripheral ghrelin signal is mediated to the brain via the vagus nerve, where it augments the release of GHRH and stimulates the secretion of neuropeptide-Y (NPY). By contrast, centrally administered ghrelin initiates a GH pulse by increasing the GHRH level and by antagonizing the SRIF block at the pituitary. In addition, NPY neurons are activated, which trigger a delayed SRIF surge. The major novel features of the present model are a) the role played by NPY, and b) the dissimilar functions of ghrelin in the hypothalamus and at the pituitary. Furthermore, the predictions of the model were experimentally examined and confirmed.
J Mol Endocrinol 2009 Sep
PMID:Interactions of ghrelin signaling pathways with the GH neuroendocrine axis: a new and experimentally tested model. 1943 92

Growth hormone (GH) transgenesis results in increased growth, feed intake and consequent metabolic rates in fish, and alters the utilization of dietary and stored carbohydrates, lipid and protein. However, the manner in which GH transgenesis differentially alters these energy sources in fish has not been well explored. We examined the effects of GH transgenesis and dietary carbohydrate, lipid and protein levels on metabolic enzyme activity in coho salmon (Oncorhynchus kisutch). In white muscle, increased activities of glycolytic enzymes and decreased activities of lipolytic enzymes in transgenic fish indicate a sparing of lipids through the preferential use of carbohydrates for energy production. In liver, transgenic fish showed increased activity of lipid synthesis enzymes and a shift in amino acid metabolism from catabolic to synthetic roles, suggesting a larger emphasis on anabolic pathways in transgenic fish to support accelerated growth. Unlike nontransgenic fish, transgenic fish fed a diet high in carbohydrates maintained growth rates, had increased capacity for lipid synthesis, and increased potential for biosynthetic roles of amino acids. GH transgenesis influences metabolic reactions in coho salmon by emphasizing carbohydrate degradation for energy production and lipid synthesis, and increasing utilization of lipids and proteins for synthetic roles necessary to maintain accelerated growth.
Comp Biochem Physiol B Biochem Mol Biol 2009 Sep
PMID:Growth hormone transgenesis influences carbohydrate, lipid and protein metabolism capacity for energy production in coho salmon (Oncorhynchus kisutch). 1947 Apr 9

Zebrafish (Danio rerio) have become an important model organism for developmental biology and human health studies. We recently demonstrated differential growth patterns between the zebrafish and a close relative the giant danio (Danio aequipinnatus), where the giant danio appears to exhibit indeterminate growth similar to most fish species important for commercial production, while zebrafish exhibit determinate growth more similar to mammalian growth. This study focused on evaluating muscle growth regulation differences in adult zebrafish and giant danio utilizing growth hormone treatment as a mode of growth manipulation. Growth hormone treatment resulted in increased overall growth in giant danio, but failed to increase growth in the zebrafish. Growth hormone treatment increased muscle IGF-I and GHrI gene expression in both species, but to a larger degree in the giant danio. In contrast, zebrafish exhibited a larger increase in IrA and IGF-IrB gene expression in muscle in response to GH treatment. In addition muscle myostatin levels were differentially regulated between the two species, with a down-regulation observed in rapidly growing, GH-treated giant danio and an up-regulation in zebrafish not actively growing in response to GH. This is the first report of differential expression of growth-regulating genes in closely related fish species exhibiting opposing growth paradigms. These results further support the role that the zebrafish and giant danio can play important model organisms for determinate and indeterminate growth.
Comp Biochem Physiol A Mol Integr Physiol 2009 Dec
PMID:Growth hormone differentially regulates growth and growth-related gene expression in closely related fish species. 1965 52

Growth hormone (GH) is the most important hormonal regulator of postnatal longitudinal growth in man. In adults GH is no longer needed for longitudinal growth. Adults with growth hormone deficiency (GHD) are characterised by perturbations in body composition, lipid metabolism, cardiovascular risk profile and bone mineral density. It is well established that adult GHD usually is accompanied by an increase in fat accumulation and GH replacement in adult patients with GHD results in reduction of fat mass and abdominal fat mass in particular. It is also recognized that obesity and abdominal obesity in particular results in a secondary reduction in GH secretion and subnormal insulin-like growth factor-I (IGF-I) levels. The recovery of the GH IGF-I axis after weight loss suggest an acquired defect, however, the pathophysiologic role of GH in obesity is yet to be fully understood. In clinical studies examining the efficacy of GH in obese subjects very little or no effect are observed with respect to weight loss, whereas GH seems to reduce total and abdominal fat mass in obese subjects. The observed reductions in abdominal fat mass are modest and similar to what can be achieved by diet or exercise interventions.
Mol Cell Endocrinol 2010 Mar 25
PMID:Obesity, growth hormone and weight loss. 1972 58

Growth hormone releasing factor (GRF) is the principal stimulatory hypothalamic neuropeptide controlling growth hormone (GH) secretion from pituitary somatotrophs. In this study we examined the hypothalamic and extrahypothalamic sites of preproGRF mRNA expression using both in situ hybridization and nuclease protection techniques. Each of these techniques confirmed that the principal site of GRF expression in CNS is within the hypothalamic arcuate nucleus with an additional population of neurons lying in the periventromedial region of the hypothalamus. PreproGRF mRNA was also detected at low levels in paraventricular and supraoptic nuclei, in piriform and neocortex, hippocampus, olfactory bulb, striatum, and brain stem, but not in anterior pituitary. However, the levels of preproGRF mRNA in these latter brain regions were approximately 20- to 50-fold lower than levels in whole hypothalamus. To extend previous observations, we then determined which brain loci modulate preproGRF mRNA levels in response to food deprivation or experimental diabetes mellitus. PreproGRF mRNA levels in both arcuate and periventromedial hypothalamic neurons declined 3- to 5-fold following food deprivation or streptozotocin-induced diabetes mellitus while the number of preproGRF expressing neurons was relatively unchanged in each experimental protocol; however, hybridization signal in piriform cortex and hippocampus was not affected by either experimental protocol. These data implicate two hypothalamic neuronal populations in modulating GH secretion and suggest specific modulation of hypothalamic preproGRF mRNA levels by food deprivation and diabetes.
Mol Cell Neurosci 1990 Dec
PMID:Localization of prepro-growth hormone releasing factor mRNA in rat brain and regulation of its content by food deprivation and experimental diabetes. 1991 69


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