An enzymatic model of the growth hormone-releasing hormone oscillator incorporating neuronal synchronization.

Models of growth hormone (GH) rhythmogenesis which we and others have presented suggest that the GH pulses in the circulation are generated by a GH-releasing hormone (GHRH) oscillator with a 1h periodicity. Here we examine the possibility that this is an intrinsic neuronal rhythm resulting from enzymatic reactions occurring in the axon terminals. A "Baselator" feedback reaction sequence can generate an hourly chemical burst of a primer (presumably a low molecular weight peptide) regulating Ca(2+)-triggered exocytosis of GHRH-loaded vesicles.

Elevated circulating acylated and total ghrelin concentrations along with reduced appetite scores in infants with failure to thrive.

Failure to thrive (FTT) is a term used to describe inadequate growth in infants. The immediate cause is undernutrition. Ghrelin is a potent orexigenic hormone that induces a positive energy balance and enhances appetite.

Subcellular dynamics of somatostatin receptor subtype 1 in the rat arcuate nucleus: receptor localization and synaptic connectivity vary in parallel with the ultradian rhythm of growth hormone secretion.

Growth hormone (GH) secretion in male rats exhibits a 3.3 h ultradian rhythm generated by the reciprocal interaction of GH-releasing hormone (GHRH) and somatostatin (SRIF). SRIF receptor subtypes sst(1) and sst(2) are highly expressed in GHRH neurons of the hypothalamic arcuate nucleus (ARC).

Interactions of ghrelin signaling pathways with the GH neuroendocrine axis: a new and experimentally tested model.

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.

Pharmacological demarcation of the growth hormone, gut motility and feeding effects of ghrelin using a novel ghrelin receptor agonist.

The peptide hormone ghrelin exerts a wide spectrum of activities including the stimulation of GH release, feeding, and gastrointestinal motility, purportedly via the activation of a common receptor, GH secretagogue receptor (since renamed the GRLN-R) The aim of the present study was to determine whether these effects can be separated pharmacologically. Tranzyme Pharma (TZP)-101 is a small-molecule agonist with potent binding affinity (inhibitory constant = 16 nm) and full agonist activity (EC50 = 29 nm, maximum response = 111%) at the human recombinant GRLN-R. Pharmacokinetic profiling of TZP-101 in rat determined a plasma elimination half-life of 99 min and low blood-brain barrier permeability (0.

Cell-cell communication in the pituitary: orchestrator of pulsatile growth hormone secretion?

Hormone secretion is dependent on intracellular and extracellular regulation of hormone synthesis and release, including classical endocrine and paracrine mechanisms and transcription factors that determine cell differentiation and hormone gene transcription. Recent research has identified direct cell-cell communication in a three-dimensional network of pituitary growth hormone-secreting cells connected by adherens junctions. This challenges the conventional view of endocrine cells as collections of dispersed cells and suggests that physical connectivity mediates cellular responses to coordinate pulsatile secretion.

Immunohistochemical distribution and subcellular localization of the somatostatin receptor subtype 1 (sst1) in the rat hypothalamus.

The aim of the present study was to examine the cellular and sub-cellular distribution of the somatostatin (SRIF) receptor subtype sst1 in the rat hypothalamus. Receptors were immunolabeled using an antibody directed against an antigenic sequence in the N-terminus of the receptor. Immunopositive neuronal cell bodies and dendrites were observed throughout the mediobasal hypothalamus, including the medial preoptic area, paraventricular, periventricular, and arcuate nuclei.

Impact of life-long macronutrient choice on neuroendocrine and cognitive functioning in aged mice: differential effects in stressor-reactive and stressor-resilient mouse strains.

Nutrient selection emerges as a result of both genetic and environmental factors and may be further modified by stressors. The impact of this complex interrelationship on pathological outcomes is poorly understood. In the present investigation the stressor-reactive BALB/cByJ and the relatively stressor resilient C57BL/6ByJ mice were maintained on a macronutrient selection protocol or given free access to chow for 20 months.

Interrelationship between the novel peptide ghrelin and somatostatin/growth hormone-releasing hormone in regulation of pulsatile growth hormone secretion.

GH is an anabolic hormone that is essential for normal linear growth and has important metabolic effects throughout life. The ultradian rhythm of GH secretion is generated by the intricate patterned release of two hypothalamic hormones, somatostatin (SRIF) and GHRH, acting both at the level of the pituitary gland and within the central nervous system. The recent discovery of ghrelin, a novel GH-releasing peptide identified as the endogenous ligand for the GH secretagogue receptor and shown to induce a positive energy balance, suggests the existence of an additional neuroendocrine pathway for GH control.

Neurochemical and behavioral alterations elicited by a chronic intermittent stressor regimen: implications for allostatic load.

Although stressors induce a series of adaptive neurochemical changes, sustained physiological activation associated with protracted stressor exposure may engender adverse effects (allostatic load). In the present investigation CD-1 mice exposed to a series of different stressors, twice a day over 54 days, exhibited increased signs of depression and anxiety, including increased passivity in a forced swim test, reduced aggression in a social interaction test, and delayed approach to food in a novel environment. Consistent with the view that a chronic stressor regimen affects immune-related processes, sickness behavior elicited by the proinflammatory cytokine, interleukin-1beta, was augmented in response to a chronic but not an acute stressor.

Temporal relationship between the sexually dimorphic spontaneous GH secretory profiles and hepatic STAT5 activity.

STAT5 transduces transcriptional responses to GH in liver and other tissues and is proposed to mediate the sexually dimorphic effects of plasma GH secretory profiles on rodent liver gene expression. Previous studies have suggested that STAT5 undergoes repeated activation in direct response to successive GH pulses in adult male rats, with STAT5 activation being desensitized in females by their more persistent pattern of GH exposure. These findings, however, were based on in vitro studies or single blood samples analyzed for GH in vivo.

mRNA expression of the IGF system in the kidney of the hypersomatotropic rat.

Aim: To examine the response of the insulinlike growth factor (IGF) system in the kidney during a state of extreme growth.

Methods: We studied the mRNA expression of IGF-I, IGF-I receptor, and IGF-binding proteins (BP) using sensitive RNase protection assays following subcutaneous implantation of growth hormone pituitary cells (GH(3)) in rats.

Results: Within 5 weeks, the serum GH levels increased from 18.

Homologous upregulation of sst2 somatostatin receptor expression in the rat arcuate nucleus in vivo.

In vitro studies using various cell systems have provided conflicting results regarding homologous regulation of somatostatin (SRIH) receptors, and information on whether SRIH regulates the expression of its own receptors in vivo is lacking. In the present study we examined, by in situ hybridization, the effects of pretreatment with the sst2-preferring SRIH analog, octreotide, in vivo, on mRNA levels of two SRIH receptor subtypes, sst1 and sst2, in rat brain and pituitary. (125)I-[DTrp(8)]-SRIH binding was also measured in these regions.

Interactions of growth hormone secretagogues and growth hormone-releasing hormone/somatostatin.

The class of novel synthetic compounds termed growth hormone secretagogues (GHSs) act in the hypothalamus through, as yet, unknown pathways. We performed physiologic and histochemical studies to further understand how the GHS system interacts with the well-established somatostatin (SRIF)/growth hormone-releasing hormone (GHRH) neuroendocrine system for regulating pulsatile GH secretion. Comparison of the GH-releasing activities of the hexapeptide growth hormone-releasing peptide-6 (GHRP-6) and GHRH administered intravenously to conscious adult male rats showed that the pattern of GH responsiveness to GHRP-6 was markedly time-dependent, similar to that observed with GHRH.

Single exposure to testosterone in adulthood rapidly induces regularity in the growth hormone release process.

The neonatal gonadal steroid milieu is known to be important in imprinting the striking sexual dimorphism of growth hormone (GH) secretion; however, the influence of the sex steroids on GH control in adult life and their mechanism/site of action are largely unknown. In the present study, we tested the hypothesis that testosterone (T) subserves the gender-specific regularity of the GH release process in adulthood. The approximate entropy statistic (ApEn) was used to quantify the degree of regularity of GH release patterns over time.

Involvement of the Sst1 somatostatin receptor subtype in the intrahypothalamic neuronal network regulating growth hormone secretion: an in vitro and in vivo antisense study.

Five somatostatin (SRIH) receptors (sst1-5) have been cloned. Recent anatomical evidence suggests that sst1 and sst2 may be involved in the central regulation of GH secretion. Given the lack of specific receptor antagonists, we used selective antisense oligodeoxynucleotides (ODNs) to test the hypothesis that one or both of these subtypes are involved in the intrahypothalamic network regulating pulsatile GH secretion.

Acute intravenous leptin infusion increases glucose turnover but not skeletal muscle glucose uptake in ob/ob mice.

The mouse ob gene encodes leptin, an adipocyte hormone that regulates body weight and energy expenditure. Leptin has potent metabolic effects on fat and glucose metabolism. A mutation of the ob gene results in mice with severe hereditary obesity and diabetes that can be corrected by treatment with the hormone.

Sexually dimorphic expression of sst1 and sst2 somatostatin receptor subtypes in the arcuate nucleus and anterior pituitary of adult rats.

The pattern of growth hormone (GH) secretion and rate of somatic growth are markedly sexually dimorphic, but the underlying neuroendocrine mechanisms are far from clear. In the present study, we tested the hypothesis that the sexual dimorphism of GH secretion may be due to gender-related differences in the transduction of somatostatin's actions in brain and/or pituitary. To accomplish this, we compared the distributional pattern and level of expression of two somatostatin receptor subtypes, sst1 and sst2, in the brain and pituitary of adult male and female rats by in-situ hybridization using 35S-labelled antisense riboprobes.

Genesis of the ultradian rhythm of GH secretion: a new model unifying experimental observations in rats.

Growth hormone (GH) induces growth in animals and humans and also has important metabolic functions. The GH neuroendocrine axis consists of a signaling cascade from the hypothalamus to the pituitary, the liver, and peripheral tissues, including two major feedback mechanisms. GH is secreted from the pituitary into the circulating blood according to the effect on the somatotrophs of two hypothalamic peptides, GH-releasing hormone (GHRH) and its antagonist, somatostatin (SRIF).

Expression of growth hormone secretagogue-receptors by growth hormone-releasing hormone neurons in the mediobasal hypothalamus.

A novel class of synthetic compounds, termed GH-secretagogues (GHSs), have been shown to be potent stimulators of GH release, although their mechanism of action and functional significance remains obscure. The recent cloning of the rat GHS receptor (GHS-R) permitted the identification of numerous sites of expression of GHS-R in brain, but nothing is yet known about the cell types that express this receptor. We performed dual chromogenic and autoradiographic in situ hybridization to test the hypothesis that GHRH neurons in the hypothalamus coexpress GHS-R mRNA.

Leptin is a potent stimulator of spontaneous pulsatile growth hormone (GH) secretion and the GH response to GH-releasing hormone.

Pulsatile GH secretion is exquisitely sensitive to perturbations in nutritional status, but the underlying mechanisms are largely unknown. Leptin, a recently discovered adipose cell hormone, is thought to be a sensor of energy stores and to regulate body mass, appetite, and metabolism at the level of the brain. Receptors for leptin are abundantly expressed in hypothalamic nuclei known to be involved in GH regulation, suggesting that leptin may serve as an important hormonal signal to the GH neuroendocrine axis in normal animals.

Growth hormone-releasing hormone neurons in the arcuate nucleus express both Sst1 and Sst2 somatostatin receptor genes.

Several lines of evidence suggest that somatostatin (SRIF) regulates GH release through central control of hypothalamic GHRH neurons. A possible mechanism is through interaction with SRIF binding sites previously shown to be associated with a subpopulation of GHRH-containing neurons in the arcuate nucleus (Arc), although the molecular identity of these binding sites is not yet known. We performed dual chromogenic and autoradiographic in situ hybridization to determine whether GHRH neurons coexpress either the sst1 and/or sst2 SRIF receptor mRNAs.

Interrelationships between somatostatin sst2A receptors and somatostatin-containing axons in rat brain: evidence for regulation of cell surface receptors by endogenous somatostatin.

Using an antipeptide antibody, we reported previously on the distribution of the somatostatin sst2A receptor subtype in rat brain. Depending on the region, immunolabeled receptors were either confined to neuronal perikarya and dendrites or distributed diffusely in tissue. To investigate the functional significance of these distribution patterns, we examined the regional and cellular relationships between somatostatin axons and sst2A receptors in the rat CNS, using double-labeling immunocytochemistry.

High-fat feeding alters both basal and stress-induced hypothalamic-pituitary-adrenal activity in the rat.

High-fat feeding induces insulin resistance and increases the risk for the development of diabetes and coronary artery disease. Glucocorticoids exacerbate this hyperinsulinemic state, rendering an individual at further risk for chronic disease. The present studies were undertaken to determine whether dietary fat-induced increases in corticosterone (B) reflect alterations in the regulatory components of the hypothalamic-pituitary-adrenal (HPA) axis.

Recombinant human growth hormone-binding protein fails to enhance the in vivo bioactivity of human growth hormone in normal rats.

GH circulates in the plasma partially bound with a GH-binding protein (GHBP), but the physiological significance of the GHBP and how it affects GH bioactivity in vivo is still unknown. In the present study, we took advantage of the known biological action of exogenous human (h) GH to inhibit endogenous rat (r) pulsatile GH release and examined the effect of combining hGH with recombinant hGHBP on this response in normal rats. Spontaneous 7-h plasma rGH and hGH profiles were obtained from four groups of free-moving adult male rats s.