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

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

Retrogradely labelled neurosecretory neurones of the rat hypothalamic arcuate nucleus express Fos protein following systemic injection of GH-releasing peptide-6

1996 ◽  
Vol 151 (2) ◽  
pp. 323-331 ◽  
Author(s):  
S L Dickson ◽  
O Doutrelant-Viltart ◽  
R E J Dyball ◽  
G Leng
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Male Rats ◽  
Cell Nuclei ◽  
Systemic Injection ◽  
Immunocytochemical Detection ◽  
Blood Brain ◽  
Fos Protein ◽  
Hypothalamic Arcuate Nucleus ◽  
Synthetic Hexapeptide

Abstract Previously, we demonstrated that the synthetic hexapeptide GH-releasing peptide (GHRP-6) activates a subpopulation of arcuate neurones, as reflected by increased electrical activation and by the detection of Fos protein in cell nuclei. Here we set out to determine (1) what proportion of the cells activated by GHRP-6 are neurosecretory neurones and (2) whether the cells activated by GHRP-6 contain tyrosine hydroxylase (TH; a marker of dopaminergic cells in this region) or β-endorphin. In the first study, adult male rats were injected i.v. with the retrograde tracer, Fluorogold, to detect cells which project outside the blood–brain barrier (and are therefore likely to be neurosecretory neurones). Three days later the conscious rats were injected i.v. with 50 μg GHRP-6 and the brains processed for the immunocytochemical detection of Fos protein. Between 68% and 82% of the arcuate neurones expressing Fos protein following GHRP-6 injection were retrogradely labelled with Fluorogold. In the second study, conscious male rats, bearing a chronically implanted jugular catheter, were killed 90 min following an i.v. injection of 50 μg GHRP-6 and the brains were processed for the double immunocytochemical detection of Fos protein and either TH or β-endorphin. Less than 7% (mean ± s.e.m.= 6·7 ± 2·6% nuclei/section per rat) of the arcuate neurones expressing Fos protein following GHRP-6 injection were TH-containing cells. Of 143β-endorphin-containing arcuate cells detected only four cells were identified as containing Fos protein. Thus, the majority of arcuate neurones activated by GHRP-6 (1) project outside the blood–brain barrier (and are therefore likely to be neurosecretory neurones) and (2) were not identified as TH- or β-endorphin-containing cells. Journal of Endocrinology (1996) 151, 323–331

Diet-derived nutrients mediate the inhibition of hypothalamic NPY neurons in the arcuate nucleus of mice during refeeding

2009 ◽  
Vol 297 (1) ◽  
pp. R100-R110 ◽  
Author(s):  
Csilla Becskei ◽  
Thomas A. Lutz ◽  
Thomas Riediger
Keyword(s):  
Neuropeptide Y ◽  
Arcuate Nucleus ◽  
Peptide Yy ◽  
Small Reduction ◽  
Hypothalamic Arcuate Nucleus ◽  
Ad Libitum ◽  
Fos Expression

Fasting activates orexigenic neuropeptide Y neurons in the hypothalamic arcuate nucleus (ARC) of mice, which is reversed by 2 h refeeding with standard chow. Here, we investigated the contribution of diet-derived macronutrients and anorectic hormones to the reversal of the fasting-induced ARC activation during 2 h refeeding. Refeeding of 12-h-fasted mice with a cellulose-based, noncaloric mash induced only a small reduction in c-Fos expression. Refeeding with diets, containing carbohydrates, protein, or fat alone reversed it similar to chow; however, this effect depended on the amount of intake. The fasting-induced ARC activation was unchanged by subcutaneously injected amylin, CCK (both 20 μg/kg), insulin (0.2 U/kg and 0.05 U/kg) or leptin (2.6 mg/kg). Insulin and leptin had no effect on c-Fos expression in neuropeptide Y or proopiomelanocortin-containing ARC neurons. Interestingly, CCK but not amylin reduced the ghrelin-induced c-Fos expression in the ARC in ad libitum-fed mice, suggesting that CCK may inhibit orexigenic ARC neurons when acting together with other feeding-related signals. We conclude that all three macronutrients and also non-nutritive, ingestion-dependent signals contribute to an inhibition of orexigenic ARC neurons after refeeding. Similar to the previously demonstrated inhibitory in vivo action of peptide YY, CCK may be a postprandial mediator of ARC inhibition.

scholarly journals Systemic ghrelin levels in subjects with growth hormone deficiency are not modified by one year of growth hormone replacement therapy

2001 ◽  
pp. 711-716 ◽  
Author(s):  
JA Janssen ◽  
FM van der Toorn ◽  
LJ Hofland ◽  
P van Koetsveld ◽  
F Broglio ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Replacement Therapy ◽  
Body Fat ◽  
Arcuate Nucleus ◽  
Gh Therapy ◽  
Percentage Body Fat ◽  
Gh Secretion ◽  
Gh Replacement ◽  
Igf I ◽  
One Year

OBJECTIVE: Ghrelin stimulates growth hormone (GH) secretion both in vivo and in vitro. Ghrelin is mainly produced in and released from the stomach but it is probably also produced in the hypothalamic arcuate nucleus. Whether pituitary GH release is under the control of ghrelin from the stomach and/or from the arcuate nucleus is not known. Moreover, no data on the feedback of GH on systemic ghrelin concentrations are available. It has recently been suggested that ghrelin may induce obesity. DESIGN: In this study, we addressed the following two questions: a) are circulating ghrelin levels increased in human GH deficiency (GHD), and b) does GH treatment modify ghrelin levels in human GHD? METHODS: The study group consisted of 23 patients with GHD. Eighteen had developed adult-onset GHD and five had developed GHD in their childhood (childhood-onset GHD). Ghrelin was measured with a commercially available radioimmunoassay. All measurements were performed twice, first at baseline, before the start of GH replacement therapy, and then again after one year of therapy. GH doses were adjusted every 3 months, targeting serum total IGF-I levels within the normal gender- and age-related reference values for the healthy population. Maintenance doses were continued once the target serum total IGF-I levels were reached. RESULTS: The sum of skinfolds and body water increased significantly, body fat mass and percentage body fat decreased significantly and body mass index and waist-hip ratio were not significantly changed by one year of GH replacement therapy.Before the start of GH replacement therapy, mean value and range for fasting ghrelin in the studied GHD subjects tended to be lower in comparison with healthy subjects in the control group although the difference did not reach significance (GHD ghrelin mean 67.8 pmol/l, range 37.6-116.3 pmol/l; control mean 83.8 pmol/l, range 35.4-132 pmol/l; P=0.11).One year of GH replacement therapy did not modify circulating ghrelin levels (ghrelin before GH therapy: 67.8 pmol/l, range 37.6-116.3 pmol/l; after GH therapy: 65.3 pmol/l, range 35.8-112.6; P=0.56). CONCLUSIONS: We did not observe elevated ghrelin levels in adult GHD subjects and GH replacement therapy did not modify circulating ghrelin levels, despite significant decreases in body fat mass and percentage body fat. It is conceivable that the lack of ghrelin modifications after long-term GH therapy was due to the reduction of adiposity and insulin on one hand, and increased GH secretion on the other. However, it is still possible that systemic ghrelin is involved in the development of obesity, both in normal and GHD subjects.

scholarly journals Ghrelin Treatment Induces Rapid and Delayed Increments of Food Intake: A Heuristic Model to Explain Ghrelin’s Orexigenic Effects

2021 ◽  
Author(s):  
Maria Paula Cornejo ◽  
Raphael Denis ◽  
Guadalupe Garcia Romero ◽  
Gimena Fernandez ◽  
Mirta Reynaldo ◽  
...  
Keyword(s):  
Food Intake ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Peptide Hormone ◽  
Heuristic Model ◽  
Feeding Response ◽  
Systemic Injection ◽  
Biphasic Effect ◽  
Nutrient Partitioning ◽  
Hypothalamic Arcuate Nucleus

Abstract Ghrelin is a stomach-derived peptide hormone with salient roles in the regulation of energy balance and metabolism. Notably, ghrelin is recognized as the most powerful known circulating orexigenic hormone. Here, we systematically investigated the effects of ghrelin on energy homeostasis and found that ghrelin primarily induces a biphasic effect on food intake that has indirect consequences on energy expenditure and nutrient partitioning. We also found that ghrelin-induced biphasic effect on food intake requires the integrity of Agouti-related peptide/neuropeptide Y-producing neurons of the hypothalamic arcuate nucleus (ARH), which seem to display a long-lasting activation after a single systemic injection of ghrelin. Finally, we found that different autonomic, hormonal and metabolic satiation signals transiently counteract ghrelin-induced food intake. Based on our observations, we propose a heuristic model to describe how the orexigenic effect of ghrelin and the anorectic food intake-induced rebound sculpt a timely constrain feeding response to ghrelin.

Ghrelin-Induced Food Intake, But not GH Secretion, Requires the Expression of the GH Receptor in the Brain of Male Mice

Endocrinology ◽  
2021 ◽  
Author(s):  
Frederick Wasinski ◽  
Franco Barrile ◽  
João A B Pedroso ◽  
Paula G F Quaresma ◽  
Willian O dos Santos ◽  
...  
Keyword(s):  
Food Intake ◽  
Arcuate Nucleus ◽  
Male Mice ◽  
Fiber Density ◽  
Gh Secretion ◽  
Gh Receptor ◽  
Fos Expression ◽  
Plasma Gh ◽  
Agouti Related Protein ◽  
The Brain

Abstract Ghrelin stimulates both growth hormone (GH) secretion and food intake. The orexigenic action of ghrelin is mainly mediated by neurons that co-express agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus (ARH). GH also stimulates food intake and, importantly, ARH AgRP/NPY neurons express GH receptor (GHR). Thus, ghrelin-induced GH secretion may contribute to the orexigenic effect of ghrelin. Here, we investigated the response to ghrelin in male mice carrying GHR ablation specifically in neurons (Brain GHR KO mice) or exclusively in ARH AgRP/NPY neurons (AgRP GHR KO mice). Although Brain GHR KO mice showed normal ghrelin-induced increase in plasma GH levels, these mutants lacked the expected orexigenic response to ghrelin. Additionally, Brain GHR KO mice displayed reduced hypothalamic levels of Npy and Ghsr mRNA and did not elicit ghrelin-induced c-Fos expression in the ARH. Furthermore, Brain GHR KO mice exhibited a prominent reduction in AgRP fiber density in the ARH and paraventricular nucleus of the hypothalamus (PVH). In contrast, AgRP GHR KO mice showed no changes in the hypothalamic Npy and Ghsr mRNAs and conserved ghrelin-induced food intake and c-Fos expression in the ARH. AgRP GHR KO mice displayed a reduced AgRP fiber density (~16%) in the PVH, but this reduction was less than that observed in Brain GHR KO mice (~61%). Our findings indicate that GHR signaling in the brain is required for the orexigenic effect of ghrelin, independently of GH action on ARH AgRP/NPY neurons.

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.

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