Hypothalamic GH-releasing Hormone Research Articles

Growth hormone-releasing hormone receptor signaling in experimental ocular inflammation and neuroprotection.

Both inflammation and anti-inflammation are involved in the protection of retinal cells. Antagonists of the hypothalamic growth hormone-releasing hormone receptor (GHRHR) have been shown to possess potent anti-inflammatory properties in experimental disease models of various organs, some with systemic complications. Such effects are also found in ocular inflammatory and neurologic injury studies. In experimental models of mice and rats, both growth hormone-releasing hormone receptor agonists and antagonists may alleviate death of ocular neural cells under certain experimental conditions. This review explores the properties of growth hormone-releasing hormone receptor agonists and antagonists that lead to its protection against inflammatory responses induced by extrinsic agents or neurologic injures in ocular animal models.

Ghrelin Gene Deletion Alters Pulsatile Growth Hormone Secretion in Adult Female Mice.

Using preproghrelin-deficient mice (Ghrl-/-), we previously observed that preproghrelin modulates pulsatile growth hormone (GH) secretion in post-pubertal male mice. However, the role of ghrelin and its derived peptides in the regulation of growth parameters or feeding in females is unknown. We measured pulsatile GH secretion, growth, metabolic parameters and feeding behavior in adult Ghrl-/- and Ghrl+/+ male and female mice. We also assessed GH release from pituitary explants and hypothalamic growth hormone-releasing hormone (GHRH) expression and immunoreactivity. Body weight and body fat mass, linear growth, spontaneous food intake and food intake following a 48-h fast, GH pituitary contents and GH release from pituitary explants ex vivo, fasting glucose and glucose tolerance were not different among adult Ghrl-/- and Ghrl+/+ male or female mice. In vivo, pulsatile GH secretion was decreased, while approximate entropy, that quantified orderliness of secretion, was increased in adult Ghrl-/- females only, defining more irregular GH pattern. The number of neurons immunoreactive for GHRH visualized in the hypothalamic arcuate nucleus was increased in adult Ghrl-/- females, as compared to Ghrl+/+ females, whereas the expression of GHRH was not different amongst groups. Thus, these results point to sex-specific effects of preproghrelin gene deletion on pulsatile GH secretion, but not feeding, growth or metabolic parameters, in adult mice.

Improvement of goose embryonic and muscular developments by wider angle egg turning during incubation and the regulatory mechanisms

Egg turning during incubation plays important roles in achieving high hatching performance and gosling quality. The objective of this study was to improve embryonic and muscular developments so to achieve better gosling quality by wider egg turning angles during incubation, and to unravel the associated regulatory molecular mechanisms. In each of three consecutive incubations, 1,728 goose eggs were divided into 3 groups that were set in the same type of commercial incubators with turning angles adjusted differently to 50°, 60°, and 70°, respectively. On average of the 3 tests, incubation with wider 70° turning angle reduced the post-18-day embryo mortality, promoted embryonic growth and development, improved the hatchability and gosling quality. On embryonic day of 29, gene mRNA expression levels of the hypothalamic growth hormone-releasing hormone (GHRH), pituitary growth hormone (GH), and liver insulin-like growth factor 1 (IGF-1) were higher in the 70° turning group than in the 50° or 60° groups. Wider angle turning also increased mRNA expression levels of the muscle development regulatory genes such as MYF5, MyoD, Myogenin (MyoG), and MRF4. Changes in expression of the above genes, together with the upregulation of the Pax3 and Pax7 genes in leg muscles, well explained the enhancement of the muscular growth and development when eggs were incubated by wider turning angles. These results also extended our understanding of the impacts and mechanisms of egg turning during incubation on hatching performance and gosling quality.

Lack of Brain Insulin Receptor Substrate-1 Causes Growth Retardation, With Decreased Expression of Growth Hormone-Releasing Hormone in the Hypothalamus.

Insulin receptor substrate-1 (Irs1) is one of the major substrates for insulin receptor and insulin-like growth factor-1 (IGF-1) receptor tyrosine kinases. Systemic Irs1-deficient mice show growth retardation, with resistance to insulin and IGF-1, although the underlying mechanisms remain poorly understood. For this study, we generated mice with brain-specific deletion of Irs1 (NIrs1KO mice). The NIrs1KO mice exhibited lower body weights, shorter bodies and bone lengths, and decreased bone density. Moreover, the NIrs1KO mice exhibited increased insulin sensitivity and glucose utilization in the skeletal muscle. Although the ability of the pituitary to secrete growth hormone (GH) remained intact, the amount of hypothalamic growth hormone-releasing hormone (GHRH) was significantly decreased and, accordingly, the pituitary GH mRNA expression levels were impaired in these mice. Plasma GH and IGF-1 levels were also lower in the NIrs1KO mice. The expression levels of GHRH protein in the median eminence, where Irs1 antibody staining is observed, were markedly decreased in the NIrs1KO mice. In vitro, neurite elongation after IGF-1 stimulation was significantly impaired by Irs1 downregulation in the cultured N-38 hypothalamic neurons. In conclusion, brain Irs1 plays important roles in the regulation of neurite outgrowth of GHRH neurons, somatic growth, and glucose homeostasis.

Interrupted IGF-1 Feedback in GHRH Neurons and Somatotrophs Results in Impaired Weight Gain and Increased Energy Expenditure

Growth hormone (GH) expression and release are thought to be primarily regulated by the counter-regulatory effects of growth hormone-releasing hormone (GHRH) and somatostatin (SST). Several reports generated in our lab and others suggest that there are other factors that regulate GH production, such as insulin-like growth factor 1 (IGF-I). Using GH-Cre recombinase targeting of the somatotroph-specific IGF-1R knockout (SIGFRKO) mouse model, we have previously demonstrated the role of IGF-1 signaling in negative feedback regulation of GH production. This model, however, presented with an incomplete phenotype, suggesting additional regulatory pathways in the hypothalamus. To provide insight into this mechanism, we have developed new transgenic mouse models that maintain the integrity of the hypothalamic-pituitary GH axis, with the single exception of IGF-IR deficiency in both hypothalamic GHRH neurons and somatotroph cells, termed GHRH-somatotroph IGF-1R knockout (G-SIFGRKO). Axiological assessments showed normal linear growth until week 14 of age, both male and female G-SIFGRKO mice presented with a significant reduction in growth velocity compared to control animals. Indirect calorimetry assessment performed at 12–14 weeks of age demonstrated that G-SIFGRKO mice had higher volume O2 consumption and lower volume CO2 production associated with increased energy expenditure than controls. The calculated respiratory exchange ratio was significantly reduced in G-SIFGRKO mice with no changes observed in either ambulatory or total activity. Furthermore, glucose and insulin tolerance tests showed no differences in glucose metabolism between G-SIFGRKO and controls. Collectively, these data provide further confirmation of the combinatorial role of IGF-1 signaling in regulating GH production and, for the first time, highlight a new GHRH-IGF-1R mediated pathway to regulate body growth and energy balance. Targeting this pathway has the potential to lead to a better understanding of the intersection between growth and metabolism and therapeutic approaches for obesity.

A Body Weight Sensor Regulates Prepubertal Growth via the Somatotropic Axis in Male Rats.

In healthy conditions, prepubertal growth follows an individual specific growth channel. Growth hormone (GH) is undoubtedly the major regulator of growth. However, the homeostatic regulation to maintain the individual specific growth channel during growth is unclear. We recently hypothesized a body weight sensing homeostatic regulation of body weight during adulthood, the gravitostat. We now investigated if sensing of body weight also contributes to the strict homeostatic regulation to maintain the individual specific growth channel during prepubertal growth. To evaluate the effect of increased artificial loading on prepubertal growth, we implanted heavy (20% of body weight) or light (2% of the body weight) capsules into the abdomen of 26-day-old male rats. The body growth, as determined by change in biological body weight and growth of the long bones and the axial skeleton, was reduced in rats bearing a heavy load compared with light load. Removal of the increased load resulted in a catch-up growth and a normalization of body weight. Loading decreased hypothalamic growth hormone releasing hormone mRNA, liver insulin-like growth factor (IGF)-1 mRNA, and serum IGF-1, suggesting that the reduced body growth was caused by a negative feedback regulation on the somatotropic axis and this notion was supported by the fact that increased loading did not reduce body growth in GH-treated rats. Based on these data, we propose the gravitostat hypothesis for the regulation of prepubertal growth. This states that there is a homeostatic regulation to maintain the individual specific growth channel via body weight sensing, regulating the somatotropic axis and explaining catch-up growth.

Substance P appears to affect growth via growth hormone-releasing hormone (GHRH) neurons in the human hypothalamus.

Substance P is an eleven-amino acid neuropeptide (undecapeptide) with multiple effects on the gastrointestinal, cardiovascular, and urinary systems as well as complex central nervous system functions such as pain, learning, memory, and sexual homeostasis. Previous studies also revealed that substance P exhibits regulatory effects on growth possibly via influencing hypothalamic GHRH release in human. However, the morphological substrate of this phenomenon has not been elucidated yet. In the present study, we examined the putative presence of juxtapositions between the substance P- and GHRH-immunoreactive (IR) systems using double-label immunocytochemistry. High-magnification light microscopy with oil immersion was used to identify putative juxtapositions between these systems. Our studies revealed substance P-IR fiber network abutting on the surface of the majority of GHRH-immunoreactive neurons in the human hypothalamus. These fiber varicosities often cover a significant surface area on the GHRH-IR neurons, forming basket-like encasements with multiple en passant type contacts. The majority of these densely innervated GHRH-IR neurons were found in the infundibular nucleus/median eminence, while substance P-IR fibers often abut on the GHRH-IR neurons in the periventricular zone and basal perifornical area of the tuberal region and in the dorsomedial subdivision of the ventromedial nucleus. The posterior hypothalamus did not contain observable substance P-GHRH associations. The density and the morphology of these intimate associations suggest that substance P influences growth by regulating hypothalamic GHRH release by direct synaptic contacts.

Brain Control of Sexually Dimorphic Liver Function and Disease: The Endocrine Connection.

A multistep signaling cascade originates in brain centers that regulate hypothalamic growth hormone-releasing hormone (Ghrh) and somatostatin expression levels and release to control the pattern of GH secretion. This process is sexually fine-tuned, and relays important information to the liver where GH receptors can be found. The temporal pattern of pituitary GH secretion, which is sex-specific in many species (episodic in males and more stable in females), represents a major component in establishing and maintaining the sexual dimorphism of hepatic gene transcription. The liver is sexually dimorphic exhibiting major differences in the profile of more than 1000 liver genes related to steroid, lipid, and foreign compound metabolism. Approximately, 90% of these sex-specific liver genes were shown to be primarily dependent on sexually dimorphic GH secretory patterns. This proposes an interesting scenario in which the central nervous system, indirectly setting GH profiles through GHRH and somatostatin control, regulates sexual dimorphism of liver activity in accordance with the need for sex-specific steroid metabolism and performance. We describe the influence of the loss of sexual dimorphism in liver gene expression due to altered brain function. Among other many factors, abnormal brain sexual differentiation, xenoestrogen exposure and D2R ablation from neurons dysregulate the GHRH-GH axis, and ultimately modify the liver capacity for adaptive mechanisms. We, therefore, propose that an inefficient brain control of the endocrine growth axis may underlie alterations in several metabolic processes through an indirect influence of sexual dimorphism of liver genes.

Serotonin Receptors of 5-HT2 Type in the Hypothalamic Arcuate Nuclei Positively Regulate Liver Cytochrome P450 via Stimulation of the Growth Hormone-Releasing Hormone/Growth Hormone Hormonal Pathway.

Our recent study carried out after local injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine into the arcuate nucleus (ARC) of the hypothalamus suggested a positive influence of the serotonergic innervation of the ARC on growth hormone (GH) secretion and GH-dependent expression of cytochrome P450. The aim of our present study was to determine the effect of the activation of the serotonin (5-HT)-type receptors, 5-HT1 or 5-HT2, in the ARC on the expression and activity of cytochrome P450 in the liver of male rats. The serotonergic agonist 5-carboxyamidotryptamine [(5-CT), a 5-HT1-type receptor agonist] or 2,5-dimethoxy-4-iodoamphetamine [(DOI), a 5-HT2-type receptor agonist] was injected into the ARC for 5 days. The activity and expression of cytochrome P450 isoenzymes and the levels of serum and pituitary hormones were estimated. DOI significantly increased the activity and expression (both mRNA and protein levels) of CYP2C11, CYP3A1/23, and CYP3A2, which positively correlated with an increase in the pituitary growth hormone-releasing hormone (GHRH) and serum GH level. The injection of 5-CT into the ARC did not affect the activity of liver P450 enzymes or hormone levels. The obtained results indicate that 5-HT2, but not the 5-HT1-type receptors in the ARC, are engaged in the positive neuroendocrine regulation of cytochrome P450, possibly by the stimulation of hypothalamic GHRH release and pituitary GH secretion, and an increase in the serum GH concentration. Further studies are going to identify which of the 5-HT2 receptor subtypes (5-HT2A, 5-HT2B, or 5-HT2C) is responsible for the observed neuroendocrine regulation of cytochrome P450.

Ghrelin stimulates growth hormone release from the pituitary via hypothalamic growth hormone-releasing hormone neurons in the cichlid, Oreochromis niloticus.

Ghrelin, a gut-brain peptide hormone, is implicated in a multiplicity of biological functions, including energy homeostasis and reproduction. Neuronal systems that are involved in energy homeostasis as well as reproduction traverse the hypothalamus; however, the mechanism by which they control energy homeostasis is not fully understood. The present study analyzes the anatomical relationship of neurons expressing gonadotropin-releasing hormone (GnRH), neuropeptide Y (NPY) and growth hormone-releasing hormone (GHRH) in a cichlid, tilapia (Oreochromis niloticus). Additionally, we examine in vivo effects of ghrelin on these hypothalamic neurons and plasma growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. Double-immunofluorescence showed neuronal fiber associations between GnRH, NPY and GHRH in the brain and pituitary. Intracerebroventricular injection of ghrelin had no effect on numbers, soma size, or optical density of GnRH and NPY neurons, whereas the number of GHRH neurons was significantly decreased in the animals injected with ghrelin when compared to controls, which may indicate administered ghrelin promoted GHRH release. Plasma GH and pituitary GH mRNA levels were significantly increased in the animals injected with ghrelin. These results suggest that central administration of ghrelin primarily act on hypothalamic GHRH neurons to stimulate GH release from the pituitary in the tilapia.

In-ovo green light photostimulation during different embryonic stages affect somatotropic axis.

Previous studies demonstrated that in-ovo photostimulation with monochromatic green light increased the somatotropic axis expression in broilers embryos. The objective of the current study was to detect the critical period for in-ovo GL photostimulation, in order to find the optimal targeted photostimulation period during the incubation process. Three hundred thirty-six fertile broiler eggs were divided into 4 groups. The first group was incubated under dark conditions as a negative control. The second incubated under intermittent monochromatic green light using light-emitting diode (LED) lamps with an intensity of 0.1 W\m2 at shell level from d 0 of the incubation as a positive control. The third group incubated under intermittent monochromatic green light from d 10 of the incubation. The last group incubated under intermittent monochromatic green light from d 15 of the incubation. In-ovo green light photostimulation from embryonic d 0 (ED0) increased plasma growth hormone (GH), as well as hypothalamic growth hormone releasing hormone (GHRH) and liver growth hormone receptor (GHR) and insulin-like growth factor-1 (IGF-1) mRNA levels. In-ovo green light photostimulation from ED10 increased the GH plasma levels compared to the negative control group, without affecting somatotropic axis mRNA genes expressions of GHRH, GHR, and IGF-1. In-ovo green light photostimulation from ED15 caused an increase in both the plasma GH levels and the somatotropic axis mRNA genes expressions of GHRH, GHR, and IGF-1, compared to the negative control group. These results suggest that the critical period of somatotropic axis acceleration by GL photostimulation start at 15 d of incubation.

Effect of the Orally Active Growth Hormone Secretagogue MK-677 on Somatic Growth in Rats.

PurposeGrowth hormone secretagogues (GHSs) possess the ability to release growth hormone (GH) in the body. This study aimed to investigate the effects of MK-677, an orally active GHS, on somatic growth in rats.Materials and MethodsThe serum levels of GH were measured after oral administration of MK-677 to confirm GH stimulatory effects. Body weight, body length, tibia length, epiphyseal plate width, and serum levels of insulin-like growth factor (IGF)-I were measured after oral administration of 4 mg/kg of MK-677 for 6 weeks to investigate growth-promoting effects.ResultsOral administration of MK-677 at 4 mg/kg increased peak GH concentrations by 1.8-fold, compared to baseline. However, oral administration of MK-677 for 6 weeks did not increase body growth or serum levels of IGF-I. At 6 weeks after treatment, the GH response to MK-677 was abolished. Pituitary GH mRNA and hypothalamic GH-releasing hormone mRNA, and GH secretagogue receptor (GHSR) mRNA expression in the pituitary and hypothalamus did not differ between the control and treatment group. Somatostatin (SST) mRNA expression in the hypothalamus was markedly increased in the treatment group, whereas SST receptor (SSTR)-2 mRNA expression in the pituitary gland was decreased. Protein expression of hypothalamic GHSR, SST, and pituitary SSTR-2 showed patterns similar to those for mRNA expression.ConclusionOur results suggest that prolonged administration of MK-677 in rats does not promote growth despite the GH stimulatory effect of MK-677, which may be related to increased expression of SST in the hypothalamus. Further studies are needed to overcome the observed desensitization to GHS.

Expression of hypothalamic neurohormones and their receptors in the human eye.

Extrapituitary roles for hypothalamic neurohormones have recently become apparent and clinically relevant, based on the use of synthetic peptide analogs for the treatment of multiple conditions including cancers, pulmonary edema and myocardial infarction. In the eye, it has been suggested that some of these hormones and their receptors may be present in the ciliary body, iris, trabecular meshwork and retina, but their physiological role has yet to be elucidated. Our study intends to comprehensively demonstrate the expression of some hypothalamic neuroendocrine hormones and their receptors within different retinal and extraretinal structures of the human eye. Immunofluorescence, Western blot analysis, and RT-PCR were used to evaluate the qualitative and quantitative expression of Luteinizing Hormone Releasing Hormone (LHRH), Growth Hormone Releasing Hormone (GHRH), Thyrotropin Releasing Hormone (TRH), Gastrin Releasing Peptide (GRP) and Somatostatin as well as their respective receptors (LHRH-R, GHRH-R, TRH-R, GRP-R, SST-R1) in cadaveric human eye tissue and in paraffinized human eye tissue sections. The hypothalamic hormones LHRH, GHRH, TRH, GRP and Somatostatin and their respective receptors (LHRH-R, GHRH-R, TRH-R, GRPR/BB2 and SST-R1), were expressed in the conjunctiva, cornea, trabecular meshwork, ciliary body, lens, retina, and optic nerve.

In-ovo monochromatic green light photostimulation enhances embryonic somatotropic axis activity

Previous studies demonstrated that in ovo photostimulation with monochromatic green light increases body weight and accelerates muscle development in broilers. The mechanism in which in ovo photostimulation accelerates growth and muscle development is not clearly understood. The objective of the current study was to define development of the somatotropic axis in the broiler embryo associated with in ovo green light photostimulation. Two-hundred-forty fertile broiler eggs were divided into 2 groups. The first group was incubated under intermittent monochromatic green light using light-emitting diode (LED) lamps with an intensity of 0.1 W\m2 at shell level, and the second group was incubated under dark conditions and served as control. In ovo green light photostimulation increased plasma growth hormone (GH) and prolactin (PRL) levels, as well as hypothalamic growth hormone releasing hormone (GHRH), liver growth hormone receptor (GHR), and insulin-like growth factor-1 (IGF-1) mRNA levels. The in ovo photostimulation did not, however, increase embryo's body weight, breast muscle weight, or liver weight. The results of this study suggest that stimulation with monochromatic green light during incubation increases somatotropic axis expression, as well as plasma prolactin levels, during embryonic development.

Corticotropin-releasing hormone (CRH)-immunoreactive (IR) axon varicosities target a subset of growth hormone-releasing hormone (GHRH)-IR neurons in the human hypothalamus

It is a general consensus that stress is one of the major factors that suppresses growth. Previous studies revealed that the catecholaminergic and neuropeptide Y (NPY) systems, involved in the activation of stress-related neuronal circuits, influence growth hormone (GH)-release via modulating growth hormone-releasing hormone (GHRH) secretion. Indeed, catecholaminergic and NPY-immunoreactive (IR) axon varicosities abut on the surface of the GHRH neurons forming contacts. These juxtapositions appear to be real synapses and may represent the morphological substrate of the impact of stress on growth. In addition to catecholamines and NPY, there is a vast amount of evidence that corticotropin-releasing hormone (CRH), a major stress hormone, also influences GH secretion. Whether this modulatory effect is direct, or indirect, via the hypothalamic GHRH system, has not been elucidated yet.In the present study, we examined the possibility that CRH influences GH secretion via modulating the GHRH release by direct synaptic mechanisms. Since the verification of these synapses by electron microscopy is problematic in human due to the long post mortem time, in order to reveal the putative CRH-GHRH juxtapositions, light microscopic double label immunohistochemistry was utilized. In the infundibular nucleus, a subset (6%) of the GHRH perikarya received abutting CRH fiber varicosities forming multiple contacts while passing by. No gaps appeared between the contacting elements. The morphology of these CRH-GHRH juxtapositions suggests that, among other neurotransmitters/neuromodulators, CRH influences growth by modulating the hypothalamic GHRH secretion via direct synaptic mechanisms.

Somatostatin triggers rhythmic electrical firing in hypothalamic GHRH neurons.

Hypothalamic growth hormone-releasing hormone (GHRH) neurons orchestrate body growth/maturation and have been implicated in feeding responses and ageing. However, the electrical patterns that dictate GHRH neuron functions have remained elusive. Since the inhibitory neuropeptide somatostatin (SST) is considered to be a primary oscillator of the GH axis, we examined its acute effects on GHRH neurons in brain slices from male and female GHRH-GFP mice. At the cellular level, SST irregularly suppressed GHRH neuron electrical activity, leading to slow oscillations at the population level. This resulted from an initial inhibitory action at the GHRH neuron level via K+ channel activation, followed by a delayed, sst1/sst2 receptor-dependent unbalancing of glutamatergic and GABAergic synaptic inputs. The oscillation patterns induced by SST were sexually dimorphic, and could be explained by differential actions of SST on both GABAergic and glutamatergic currents. Thus, a tripartite neuronal circuit involving a fast hyperpolarization and a dual regulation of synaptic inputs appeared sufficient in pacing the activity of the GHRH neuronal population. These “feed-forward loops” may represent basic building blocks involved in the regulation of GHRH release and its downstream sexual specific functions.

Surgical castration but not immuncastration is associated with reduced hypothalamic GnIH and GHRH/GH/IGF-I axis function in male rats

Gonadotropin-inhibitory hormone (GnIH) is a potent positive regulator of the growth axis. The present study was aimed to comparatively investigate the effects of surgical and immunologic castration on hypothalamic GnIH expression and endocrine function of the growth axis. Thirty-six prepubertal male rats were randomly allocated into three groups (n = 12): control, surgically castrated or immunized against 100-μg D-Lys6-GnRH-tandem peptide conjugated to ovalbumin in Specol adjuvant at 6 weeks of age (with a booster 8 weeks later). Blood samples were collected (for hormone and urea nitrogen concentrations) at 2-week intervals, and growth performance was evaluated. Compared to intact controls, surgical castration reduced (P < 0.05) messenger RNA (mRNA) expressions of hypothalamic GnIH and growth hormone–releasing hormone (GHRH), pituitary growth hormone (GH), and liver insulin-like growth factor-1 (IGF-1), reduced (P < 0.05) serum concentrations of GH and IGF-1 and increased (P < 0.05) serum concentrations of urea nitrogen. In contrast, immunocastration did not alter messenger RNA expressions of hypothalamic GnIH, GHRH and pituitary GH, and the serum concentrations of GH (P > 0.05). Moreover, serum concentrations of IGF-1 and urea nitrogen in immunocastrates were substantially higher and lower than those in surgical castrates, respectively (P < 0.05). Compared to surgical castrates, immuncastrates had superior feed conversion efficiency and faster daily weight gain (P < 0.05). We concluded that surgical castration but not immunocastration is associated with reduced hypothalamic GnIH and GHRH/GH/IGF-I axis function in male rats.

Role of growth hormone-releasing hormone in dyslipidemia associated with experimental type 1 diabetes

Dyslipidemia associated with triglyceride-rich lipoproteins (TRLs) represents an important residual risk factor for cardiovascular and chronic kidney disease in patients with type 1 diabetes (T1D). Levels of growth hormone (GH) are elevated in T1D, which aggravates both hyperglycemia and dyslipidemia. The hypothalamic growth hormone-releasing hormone (GHRH) regulates the release of GH by the pituitary but also exerts separate actions on peripheral GHRH receptors, the functional role of which remains elusive in T1D. In a rat model of streptozotocin (STZ)-induced T1D, GHRH receptor expression was found to be up-regulated in the distal small intestine, a tissue involved in chylomicron synthesis. Treatment of T1D rats with a GHRH antagonist, MIA-602, at a dose that did not affect plasma GH levels, significantly reduced TRL, as well as markers of renal injury, and improved endothelial-dependent vasorelaxation. Glucagon-like peptide 1 (GLP-1) reduces hyperglucagonemia and postprandial TRL, the latter in part through a decreased synthesis of apolipoprotein B-48 (ApoB-48) by intestinal cells. Although plasma GLP-1 levels were elevated in diabetic animals, this was accompanied by increased rather than reduced glucagon levels, suggesting impaired GLP-1 signaling. Treatment with MIA-602 normalized GLP-1 and glucagon to control levels in T1D rats. MIA-602 also decreased secretion of ApoB-48 from rat intestinal epithelial cells in response to oleic acid stimulation in vitro, in part through a GLP-1-dependent mechanism. Our findings support the hypothesis that antagonizing the signaling of GHRH in T1D may improve GLP-1 function in the small intestine, which, in turn, diminishes TRL and reduces renal and vascular complications.

Growth hormone modulates hypothalamic inflammation in long-lived pituitary dwarf mice.

Mice in which the genes for growth hormone (GH) or GH receptor (GHR(-/-) ) are disrupted from conception are dwarfs, possess low levels of IGF-1 and insulin, have low rates of cancer and diabetes, and are extremely long-lived. Median longevity is also increased in mice with deletion of hypothalamic GH-releasing hormone (GHRH), which leads to isolated GH deficiency. The remarkable extension of longevity in hypopituitary Ames dwarf mice can be reversed by a 6-week course of GH injections started at the age of 2 weeks. Here, we demonstrate that mutations that interfere with GH production or response, in the Snell dwarf, Ames dwarf, or GHR(-/-) mice lead to reduced formation of both orexigenic agouti-related peptide (AgRP) and anorexigenic proopiomelanocortin (POMC) projections to the main hypothalamic projection areas: the arcuate nucleus (ARH), paraventricular nucleus (PVH), and dorsomedial nucleus (DMH). These mutations also reduce hypothalamic inflammation in 18-month-old mice. GH injections, between 2 and 8 weeks of age, reversed both effects in Ames dwarf mice. Disruption of GHR specifically in liver (LiGHRKO), a mutation that reduces circulating IGF-1 but does not lead to lifespan extension, had no effect on hypothalamic projections or inflammation, suggesting an effect of GH, rather than peripheral IGF-1, on hypothalamic development. Hypothalamic leptin signaling, as monitored by induction of pStat3, is not impaired by GHR deficiency. Together, these results suggest that early-life disruption of GH signaling produces long-term hypothalamic changes that may contribute to the longevity of GH-deficient and GH-resistant mice.

Juxtapositions between the somatostatinergic and growth hormone-releasing hormone (GHRH) neurons in the human hypothalamus

Somatostatin is a 14–28 amino acid peptide that is located not only in the gastrointestinal system but also in multiple sites of the human brain. The inhibitory effect of somatostatin on the growth hormone (GH) secretion of the pituitary gland is a well-established phenomenon. There is a general consensus that somatostatin is released into the hypophysial portal blood and modulates GH secretion by hormonal action. In the present study, we explored the possibility that in addition to the hormonal route, somatostatin may also influence GH secretion via influencing the growth hormone-releasing hormone (GHRH) secretion by direct contacts that may be functional synapses.Since the verification of these putative synapses by electron microscopy is virtually impossible in humans due to the long post mortem time, in order to reveal the putative somatostatinergic-GHRH juxtapositions, light microscopic double-label immunohistochemistry was utilized.By examining the slides with high magnification, we observed that the vast majority of the GHRH perikarya received contacting somatostatinergic axonal varicosities in the arcuate nucleus. In contrast, GHRH axonal varicosities rarely contacted somatostatinergic perikarya.The morphology and the abundance of somatostatin to GHRH juxtapositions indicate that these associations are functional synapses, and they represent, at least partially, the morphological substrate of the somatostatin-influenced GHRH secretion. Thus, in addition to influencing the GH secretion directly via the hypophysial portal system, somatostatin may also modulate GH release from the anterior pituitary by regulating the hypothalamic GHRH secretion via direct contacts. The rare GHRH to somatostatin juxtapositions indicate that the negative feedback effect of GH targets the somatostatinergic system directly and not via the GHRH system.