Neuroendocrine Control of Growth Hormone Secretion

Müller, Eugenio E.; Locatelli, Vittorio; Cocchi, Daniela

doi:10.1152/physrev.1999.79.2.511

Cited by 587 publications

(530 citation statements)

References 919 publications

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“…Our results suggest that obese A y /a mice have reduced hypothalamic somatostatin peptide content and PeVN somatostatin mRNA expression. Since somatostatin inhibits the somatotrophic axis and hypophysiotrophic somatostatin neurones are located in the PeVN, 14 a reduction in PeVN somatostatin would be expected to result in increased plasma GH and hence IGFI. In accord with this, plasma IGFI and GH concentrations were increased in obese A y /a mice, although the latter not significantly.…”

Section: Discussionmentioning

confidence: 99%

“…Hypophysiotrophic somatostatin neurones located in the periventricular nucleus (PeVN) inhibit GH release. 14 Signals regulating energy balance have also been implicated in the regulation of the somatotrophic axis, suggesting that coordinated regulation of growth occurs when energy stores are sufficient. Systemically administered ghrelin stimulates food intake and is a potent GH secretagogue (GHS) in rats and humans.…”

Section: Introductionmentioning

confidence: 99%

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Abnormalities of the somatotrophic axis in the obese agouti mouse

et al. 2005

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Objective: Abnormalities of the melanocortin system produce obesity and increased linear growth. While the obesity phenotype is well characterised, the mechanism responsible for increased linear growth is unclear. The somatotrophic axis was studied in the obese agouti (A y /a) mouse as a model of a perturbed melanocortin system. Design: Adult obese A y /a mice were compared to age-and sex-matched wild-type (WT) controls. Weight and body length (nose-anus) were recorded. Plasma growth hormone (GH), insulin-like growth factor-I (IGFI), insulin and leptin were measured using radioimmunoassay. Since ghrelin is a potent GH secretagogue, plasma ghrelin, stomach ghrelin peptide and stomach ghrelin mRNA expression were studied. Hypothalamic periventricular (PeVN) somatostatin neurones and arcuate (Arc) neuropeptide Y (NPY) neurones inhibit the growth axis, whereas Arc growth hormone-releasing hormone (GHRH) neurones are stimulatory. Therefore, specific hypothalamic expression of somatostatin, NPY and GHRH was measured using quantitative in situ hybridisation. Results: Obese A y /a mice were significantly heavier and longer than WT controls. Plasma IGFI concentrations were 30% greater in obese A y /a mice. Obese A y /a mice were hyperinsulinaemic and hyperleptinaemic, yet plasma ghrelin, and stomach ghrelin peptide and mRNA were significantly reduced. In obese A y /a mice, PeVN somatostatin and Arc NPY mRNA expression were reduced by 50% compared to WT controls, whereas Arc GHRH mRNA expression was unchanged. Conclusion: Increased body length in adult obese A y /a mice may result from reduced Arc NPY and PeVN somatostatin mRNA expression, which in turn, may increase plasma IGFI concentrations and upregulate the somatotrophic axis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Abnormalities of the somatotrophic axis in the obese agouti mouse

et al. 2005

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“…Cardiotropic activities are also exerted by other molecules known as GH secretagogues (GHS) that are distinct entities from GHRH, the endogenous hypophysiotropic neurohormone stimulating somatotroph secretion (Ghigo et al, 1997;Müller et al, 1999). GHS were discovered as a family of non-natural peptidyl and non-peptidyl molecules able to strongly stimulate GH secretion acting on a specific Gprotein coupled receptor, namely GHS type 1a receptor, that is different from the GHRH-receptor (Smith et al, 1997;Muccioli et al, 1998Muccioli et al, , 2002.…”

Section: Introductionmentioning

confidence: 99%

Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Bedendi

Alloatti

Marcantoni

et al. 2003

European Journal of Pharmacology

169

116

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The mechanisms underlying the cardiac activities of synthetic growth hormone secretagogues (GHS) are still unclear. The natural ligand of the GHS receptors, i.e. ghrelin, classically binds the GHS receptor and exerts endocrine actions in acylated forms only; its cardiovascular actions still need to be investigated further. In order to clarify these aspects, we studied the effects of either the synthetic peptidyl GHS hexarelin (1 AM), or the natural ghrelin (50 nM) and the endogenous ghrelin derivatives des-Gln 14 -ghrelin (1 -100 nM) and des-octanoyl ghrelin (50 nM), on the tension developed by guinea pig papillary muscle and on L-type Ca 2 + current (I Ca ) of isolated ventricular cells. The binding of these molecules to ventricular cell membrane homogenates was also studied. We observed that all peptides reduced the tension developed at low frequencies (60 -120 beats/min) in a dose-dependent manner. No alteration in cardiac contractility was induced by desGln 14 -ghrelin or des-octanoylated ghrelin when the endocardial endothelium had been removed or after cyclooxygenase blockade. Pretreatment with tyramine (2 AM) had no effect on the inotropic response induced by des-Gln 14 -ghrelin. No significant effect on I Ca of isolated ventricular cells was observed in the presence of des-Gln 14 -ghrelin (100 nM). The order of potency on the tension of papillary muscle was: des-octanoyl ghrelin>ghrelin = des-Gln 14 -ghrelin>hexarelin. This gradient of potency was consistent with the binding experiments performed on ventricular membranes where either acylated or unacylated ghrelin forms, and hexarelin, recognized a common high-affinity binding site. In conclusion, ghrelin, des-Gln 14 -ghrelin and des-octanoyl ghrelin, show similar negative inotropic effect on papillary muscle; as des-octanoyl ghrelin is peculiarly devoid of any GH-releasing activity, the cardiotropic action of these molecules is independent of GH release. The binding studies and the experiments performed both on the isolated cells and on papillary muscle after endothelium removal or cyclooxygenase blockade indicate that the cardiotropic action of natural and synthetic ghrelin analogues reflects the interaction with a novel GHS receptor (peculiarly common for ghrelin and des-octanoyl ghrelin), leading to release of cyclooxygenase metabolites from endothelial cells, as indicated by direct measurement of prostacyclin metabolite 6-keto-PGF 1a .

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“…The arcuate nucleus of the hypothalamus (ARH) contains neurons that produce the anorexigenic peptide melanocyte‐stimulating hormone (MSH) and other neurons that coexpress the orexigenic peptides neuropeptide Y (NPY) and agouti‐related protein (AgRP), which regulate food intake and energy expenditure (Myers, 2004). The ARH neurons interact with pituitary cells that produce GH, through the opposing actions of somatostatin (SS) and GH‐releasing hormone (GHRH), derived from the periventricular nucleus and ARH of the hypothalamus (Muller et al ., 1999). Systemic administration of GH induces expression of the c‐fos gene, a marker of neuronal activity, in the hypothalamic NPY and somatostatin neurons (Kamegai et al ., 1994).…”

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confidence: 99%

Growth hormone modulates hypothalamic inflammation in long‐lived pituitary dwarf mice

et al. 2015

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SummaryMice 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.

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Neuroendocrine Control of Growth Hormone Secretion

Cited by 587 publications

References 919 publications

Abnormalities of the somatotrophic axis in the obese agouti mouse

Abnormalities of the somatotrophic axis in the obese agouti mouse

Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Growth hormone modulates hypothalamic inflammation in long‐lived pituitary dwarf mice

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