Microinjection of rat GH but not human IGF-I into a defined area of the hypothalamus inhibits endogenous GH secretion in rats

1997 ◽  
Vol 153 (2) ◽  
pp. 283-290 ◽  
Author(s):  
S Minami ◽  
N Suzuki ◽  
H Sugihara ◽  
H Tamura ◽  
N Emoto ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Male Rats ◽  
Gh Secretion ◽  
Receptor Mrna ◽  
Gh Receptor ◽  
Periventricular Nucleus ◽  
Igf I ◽  
Hypothalamic Arcuate Nucleus ◽  
Somatostatin Neurons ◽  
Secretory Pattern

Abstract It has been surmised that GH exerts feedback action on the hypothalamus and thereby regulates its own secretion. Our previous studies suggested that GH acts on somatostatin neurons in the hypothalamic periventricular nucleus (PeV) and neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC). However, there remains uncertainty whether GH acts directly or indirectly through the generation of IGFs on the hypothalamus to regulate its own secretion. To examine this, rat GH (rGH) or human IGF-I was injected directly into a defined area of the hypothalamus, and the blood GH profile was observed in conscious male rats. In the rats given 0·5 μg rGH into the ARC or PeV bilaterally, GH secretion was inhibited, and the inhibition lasted for 12 h. During the period of inhibition, the duration and amplitude of GH pulses were significantly decreased and the episodic secretion of GH appeared irregularly compared with the vehicle-injected control rats. In control rats given the vehicle or those given rGH into the lateral hypothalamus, the blood GH profile did not change and pulsatile GH secretion was produced every 3 h. When 0·1 μg IGF-I was injected into the ARC or PeV bilaterally, the blood GH secretory pattern was not affected. Together with the results of our previous studies showing that c-fos gene expression was induced by systemic administration of GH and that GH receptor mRNA was contained in somatostatin neurons in the PeV and NPY neurons in the ARC, the data of the present study indicate that GH, but not IGF-I, acts on the cells in the ARC and the PeV or in their vicinity to inhibit its own secretion, presumably by activating the somatostatin and NPY neurons. Journal of Endocrinology (1997) 153, 283–290

GH-deficient dw/dw rats and lit/lit mice show increased Fos expression in the hypothalamic arcuate nucleus following systemic injection of GH-releasing peptide-6

1995 ◽  
Vol 146 (3) ◽  
pp. 519-526 ◽  
Author(s):  
S L Dickson ◽  
O Doutrelant-Viltart ◽  
G Leng
Keyword(s):  
Arcuate Nucleus ◽  
Direct Action ◽  
Cell Nuclei ◽  
Systemic Injection ◽  
Gh Secretion ◽  
Fos Protein ◽  
Igf I ◽  
Hypothalamic Arcuate Nucleus ◽  
Central Actions ◽  
Fos Expression

Abstract In the rat, the synthetic GH secretagogue GH-releasing peptide (GHRP-6) acts centrally to activate a subpopulation of arcuate neurones as reflected by increased electrical activation and by the detection of Fos protein in cell nuclei. Since GHRP-6 also induces GH secretion via a direct action on the pituitary, we set out to determine whether the central actions of GHRP-6 are mediated by GH itself. First, we demonstrated that peripherally administered GHRP-6 induces Fos expression in the arcuate nucleus of GH-deficient animals (dw/dw rats and lit/lit mice). Secondly, in dw/dw rats, neither intracerebro-ventricular injection of 15 μg recombinant bovine GH nor 1 μg recombinant human IGF-I resulted in an increase in the number of cells expressing Fos protein in the arcuate nucleus (or in any other hypothalamic structure studied). These results support our hypothesis that GHRP-6 has a central site and mechanism of action and provide evidence to suggest that the activation of arcuate neurones by GHRP-6 is not mediated by a central action of GH or IGF-I. Furthermore, since the lit/lit mouse pituitary does not release GH following GHRP-6 administration, our finding that the central actions of GHRP-6 remain intact in these animals suggests the possible existence of two subpopulations of putative GHRP-6 receptors. Journal of Endocrinology (1995) 146, 519–526

scholarly journals Ghrelin Stimulates GH But Not Food Intake in Arcuate Nucleus Ablated Rats

Endocrinology ◽  
2002 ◽  
Vol 143 (9) ◽  
pp. 3268-3275 ◽  
Author(s):  
Hideki Tamura ◽  
Jun Kamegai ◽  
Takako Shimizu ◽  
Shinya Ishii ◽  
Hitoshi Sugihara ◽  
...  
Keyword(s):  
Food Intake ◽  
Normal Control ◽  
Arcuate Nucleus ◽  
Monosodium Glutamate ◽  
Male Rats ◽  
Appetite Control ◽  
Gh Secretion ◽  
Increase Food Intake ◽  
Hypothalamic Arcuate Nucleus ◽  
Plasma Gh

Abstract Ghrelin, an endogenous ligand for the GH secretagogue receptor 1a (GHS-R1a), was originally purified from the rat stomach. Ghrelin mRNA and peptide have also been detected in the hypothalamus and pituitary. Ghrelin is a novel acylated peptide that regulates GH release and energy metabolism. GHS-R1a mRNA is expressed in the pituitary gland as well as in several areas of the brain including the hypothalamus. In this study, we examined whether ghrelin could stimulate GH secretion and feeding in chronic GHRH, neuropeptide Y, and agouti-related protein deficient rats that were neonatally treated with monosodium glutamate (MSG), which destroys the neurons in the hypothalamic arcuate nucleus (ARC). Intravenous (iv) administration of rat ghrelin (10 μg/kg body weight) increased plasma GH levels significantly in the normal adult male rats during a GH trough period of pulsatile GH secretion, while iv injection of ghrelin in MSG-treated rats resulted in a markedly attenuated GH response. When rat ghrelin (10 μg/rat) was administered intracerebroventricular (icv), plasma GH levels were increased comparably in normal control and MSG-treated rats. However, the GH release after icv injection of ghrelin was markedly diminished compared with that after iv administration of a small amount of ghrelin in normal control rats (icv: 10 μg/rat, iv: approximately 4.0 μg/rat), indicating that the GH-releasing activity of exogenous ghrelin is route dependent and at least in part via hypothalamic ARC. The icv administration of 1 μg of ghrelin increased significantly 4-h food intake in normal control, whereas the peptide did not increase food intake in MSG-treated rats, indicating that the feeding response to ghrelin requires intact ARC. Taken together, the primary action of ghrelin on appetite control and GH releasing activity is via the ARC even though it might act on another type of GHS-R besides GHS-R1a.

Regulation of porcine insulin-like growth factor I and growth hormone receptor mRNA expression by energy status

1994 ◽  
Vol 266 (5) ◽  
pp. E776-E785 ◽  
Author(s):  
P. A. Weller ◽  
M. J. Dauncey ◽  
P. C. Bates ◽  
J. M. Brameld ◽  
P. J. Buttery ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Growth Rates ◽  
Mrna Levels ◽  
Energy Status ◽  
Factor I ◽  
Receptor Mrna ◽  
Gh Receptor ◽  
Igf I ◽  
Class 1

Regulation of insulin-like growth factor I (IGF-I) and growth hormone (GH) receptor mRNA in liver and muscle by energy status was assessed in 2-mo-old pigs by altering thermoregulatory demand and energy intake over a 5-wk period to produce a range of plasma IGF-I concentrations from 3.5 +/- 0.7 to 28.9 +/- 6.2 nmol/l. These values were related directly to growth rates (0.06 +/- 0.02 to 0.44 +/- 0.01 kg/day) and total hepatic IGF-I mRNA levels. Increased growth rates were accompanied by an increase in hepatic class 1 and class 2 IGF-I mRNA levels and an increase in the ratio of class 2 to class 1 IGF-I mRNA in liver, suggesting a distinct role for class 2 expression in the endocrine growth response. High levels of class 1 transcripts and a virtual absence of class 2 transcripts characterized all muscle tissues examined, and there was no correlation with plasma IGF-I levels. This suggests that growth promotion in response to increased energy status is regulated via endocrine hepatic IGF-I rather than via a paracrine response. The levels of GH receptor mRNA were positively correlated with overall growth rate (P < 0.005) in liver and negatively correlated (P < 0.05) in muscle, indicating distinct tissue-specific effects of energy status.

scholarly journals A Paradoxical Gender Dissociation within the Growth Hormone/Insulin-Like Growth Factor I Axis during Protracted Critical Illness1

2000 ◽  
Vol 85 (1) ◽  
pp. 183-192
Author(s):  
G. Van den Berghe ◽  
R. C. Baxter ◽  
F. Weekers ◽  
P. Wouters ◽  
C. Y. Bowers ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Critical Illness ◽  
Critically Ill ◽  
Approximate Entropy ◽  
Female Patients ◽  
Gh Secretion ◽  
Factor I ◽  
Igf I ◽  
Male Patients ◽  
Secretory Pattern

Female gender appears to protect against adverse outcome from prolonged critical illness, a condition characterized by blunted and disorderly GH secretion and impaired anabolism. As a sexual dimorphism in the GH secretory pattern of healthy humans and rodents determines gender differences in metabolism, we here compared GH secretion and responsiveness to GH secretagogues in male and female protracted critically ill patients. GH secretion was quantified by deconvolution analysis and approximate entropy estimates of 9-h nocturnal time series in 9 male and 9 female patients matched for age (mean ± sd, 67 ± 11 and 67 ± 15 yr), body mass index, severity and duration of illness, feeding, and medication. Serum concentrations of PRL, TSH, cortisol, and sex steroids were measured concomitantly. Serum levels of GH-binding protein, insulin-like growth factor I (IGF-I), IGF-binding proteins (IGFBPs), and PRL were compared with those of 50 male and 50 female community-living control subjects matched for age and body mass index. In a second study, GH responses to GHRH (1 μg/kg), GH-releasing peptide-2 (GHRP-2; 1 μg/kg) and GHRH plus GHRP-2 (1 and 1 μg/kg) were examined in comparable, carefully matched male (n = 15) and female (n = 15) patients. Despite identical mean serum GH concentrations, total GH output, GH half-life, and number of GH pulses, critically ill men paradoxically presented with less pulsatile (mean ± sd pulsatile GH fraction, 39 ± 14% vs. 67 ± 20%; P = 0.002) and more disorderly (approximate entropy, 0.946 ± 0.113 vs. 0.805 ± 0.147; P = 0.02) GH secretion than women. Serum IGF-I, IGFBP-3, and acid-labile subunit (ALS) levels were low in patients compared with controls, with male patients revealing lower IGF-I (P = 0.01) and ALS (P = 0.005) concentrations than female patients. Correspondingly, circulating IGF-I and ALS levels correlated positively with pulsatile (but not with nonpulsatile) GH secretion. Circulating levels of GH-binding protein and IGFBP-1, -2, and -6 were higher in patients than controls, without a detectable gender difference. In female patients, PRL levels were 3-fold higher, and TSH and cortisol tended to be higher than levels in males. In both genders, estrogen levels were more than 3-fold higher than normal, and testosterone (2.25 ± 1.94 vs. 0.97 ± 0.39 nmol/L; P = 0.03) and dehydroepiandrosterone sulfate concentrations were low. In male patients, low testosterone levels were related to reduced GH pulse amplitude (r = 0.91; P = 0.0008). GH responses to GHRH were relatively low and equal in critically ill men and women (7.3 ± 9.4 vs. 7.8 ± 4.1 μg/L; P = 0.99). GH responses to GHRP-2 in women (93 ± 38 μg/L) were supranormal and higher (P &lt; 0.0001) than those in men (28 ± 16 μg/L). Combining GHRH with GHRP-2 nullified this gender difference (77 ± 58 in men vs. 120 ± 69 μg/L in women; P = 0.4). In conclusion, a paradoxical gender dissociation within the GH/IGF-I axis is evident in protracted critical illness, with men showing greater loss of pulsatility and regularity within the GH secretory pattern than women (despite indistinguishable total GH output) and concomitantly lower IGF-I and ALS levels. Less endogenous GHRH action in severely ill men compared with women, possibly due to profound hypoandrogenism, accompanying loss of the putative endogenous GHRP-like ligand action with prolonged stress in both genders may explain these novel findings.

Degenerative changes of the Medial arcuate hypothalamic nucleus neurons in the male hypogonadism model

2015 ◽  
Vol 6 (3) ◽  
pp. 62-68
Author(s):  
Yulia Nikolaevna Khodulaeva ◽  
Zakhar Petrovich Asaulenko ◽  
Alekber Azizovoch Baymarov ◽  
Irina Leorovna Nikitina ◽  
Andreiy Vsevolodovich Droblenkov
Keyword(s):  
Hormonal Regulation ◽  
Structural Changes ◽  
Arcuate Nucleus ◽  
Male Rats ◽  
Hypothalamic Nucleus ◽  
Control Group ◽  
Male Hypogonadism ◽  
Testosterone Therapy ◽  
Reactive Changes ◽  
Hypothalamic Arcuate Nucleus

The study of patterns of hormonal regulation of sexual development of adolescents including mechanisms of physiological and pathological changes in the rate of maturation of the hypothalamic-pituitary-gonadal axis remains the subject of active research interest. The study of reactive changes of the medial arcuate nucleus of cells in experimental hypogonadism and degree of correction of these changes after testosterone therapy is necessary for a better understanding of the mechanisms of endocrine interaction gonads and gonadoliberin centers during puberty. The aim of this article was to determine the quantitative, structural changes of neurons, glio-neuronal and interneuronal relationships in the medial arcuate nucleus in experimental hypogonadism and the degree of correction of these changes after testosterone therapy. In male Wistar rats induced hypogonadism (model created by the removal of one gonad on postnatal day 2-3), and histological sections were examined medial hypothalamic arcuate nucleus puberty animals (2 months) and the absence of treatment with testosterone after correction. The control group consisted of intact animals puberty. It was found that after the experimental inhibition of testosterone production in newborn male rats in the medial hypothalamic arcuate nucleus of rat puberty develop degenerative (degenerative, atrophic) and compensatory-adaptive changes. First expressed in the reduction of the share and the decrease in the normochromic neurons area, wrinkling, the growth of the share of shadowly neurons. The latter expressed signs of activation glio-neuronal and interneuronal relations. Many reactive changes in the cells exposed to compensatory adjustment in the period of puberty.

Growth hormone (GH)-binding protein in normal and GH-deficient dwarf rats

1992 ◽  
Vol 135 (3) ◽  
pp. 447-457 ◽  
Author(s):  
D. F. Carmignac ◽  
T. Wells ◽  
L. M. S. Carlsson ◽  
R. G. Clark ◽  
I. C. A. F. Robinson
Keyword(s):  
Continuous Infusion ◽  
Physiological Role ◽  
Female Rats ◽  
Small Samples ◽  
Somatostatin Analogue ◽  
Adult Rats ◽  
Gh Secretion ◽  
Gh Receptor ◽  
Secretory Pattern ◽  
Dwarf Males

ABSTRACT There are GH-binding proteins (GHBPs) present in the blood of many species, and these correspond to the extracellular GH-binding domain of the GH receptor. In the rat, GHBP arises by alternative splicing of the GH receptor mRNA, but little is known of the physiological role of circulating GHBP, or its relationship with episodic GH secretion. We have developed a sensitive radioimmunoassay based on recombinant GHBP, and have measured rat GHBP levels in small samples of plasma from normal and GH-deficient dwarf rats. In normal adult rats, GHBP levels were two- to threefold higher in females than in males (16·6 ± 0·8 vs 6·4 ± 0·4μg/l, P < 0·001), but this sex difference was not seen in dwarf rats. A continuous infusion of human GH in dwarf males raised plasma GHBP to 23·5 ± 3·5 μg/l compared with 6·7 ± 0·5 μg/l in sham-infused animals, whereas suppression of GH by continuous infusion of a long-acting somatostatin analogue in female dwarf rats had no effect on GHBP. In anaesthetized rats, large changes in plasma GH caused by i.v. administration of rat GH, somatostatin or GH-releasing factor did not affect GHBP acutely. Both GH and GHBP were also measured in serial blood samples from conscious normal and dwarf rats. A sexually dimorphic GH secretory pattern was observed in both strains. Males showed peaks and troughs of GH every 3 h varying over a 100-fold range, whereas females exhibited more continuous GH secretion. Despite the large fluctuations in endogenous GH, GHBP levels remained relatively constant in individual normal or dwarf males, as well as in females of both strains, and there was no significant correlation between GH and GHBP either in individual rats or as a group. Our results suggest that GHBP is GH-dependent in the longer term, and that the higher GHBP levels in female rats require their continuous GH secretory pattern. However, plasma GHBP levels remain stable and are not affected by acute changes in endogenous or exogenous GH. Journal of Endocrinology (1992) 135, 447–457

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