Rapid desensitisation of the GH secretagogue (ghrelin) receptor to hexarelin in vitro

Orkin, R. D.; New, David; Norman, Dennis; Chew, Shern L.; Clark, Adrian; Grossman, Ashley; Korbonits, M

doi:10.1007/bf03347357

Cited by 20 publications

(10 citation statements)

References 34 publications

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“…Previous data found no change in CB 1 binding in the hypothalamus after acute or chronic stimulation, while other brain areas show variable down-and up-regulation after acute and chronic CB 1 agonist THC administration (54). The downregulation of GHS-R1a is in accordance with earlier desensitization studies and also corresponds with in vivo data following repeated GHS-R agonist administration (55)(56)(57); however, upregulation of hypothalamic GHS-R has also been described after ghrelin administration (28). Desacyl ghrelin, which does not activate GHS-R1a, has similar adipogenic effects to ghrelin on adipose cells, suggesting the involvement of an alternative receptor (10).…”

Section: Discussionsupporting

confidence: 89%

Cannabinoids and Ghrelin Have Both Central and Peripheral Metabolic and Cardiac Effects via AMP-activated Protein Kinase

Kola

Hubina

Tucci

et al. 2005

Journal of Biological Chemistry

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441

333

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Endocannabinoids and ghrelin are potent appetite stimulators and are known to interact at a hypothalamic level. However, both also have important peripheral actions, including beneficial effects on the ischemic heart and increasing adipose tissue deposition, while ghrelin has direct effects on carbohydrate metabolism. The AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that functions as a fuel sensor to regulate energy balance at both cellular and whole body levels, and it may mediate the action of anti-diabetic drugs such as metformin and peroxisome proliferator-activated receptor ␥ agonists. Here we show that both cannabinoids and ghrelin stimulate AMPK activity in the hypothalamus and the heart, while inhibiting AMPK in liver and adipose tissue. These novel effects of cannabinoids on AMPK provide a mechanism for a number of their known actions, such as the reduction in infarct size in the myocardium, an increase in adipose tissue, and stimulation of appetite. The beneficial effects of ghrelin on heart function, including reduction of myocyte apoptosis, and its effects on lipogenesis and carbohydrate metabolism, can also be explained by its ability to activate AMPK. Our data demonstrate that AMPK not only links the orexigenic effects of endocannabinoids and ghrelin in the hypothalamus but also their effects on the metabolism of peripheral tissues.Endocannabinoids, acting via the presynaptic cannabinoid type 1 receptor (CB 1 ), 1 stimulate appetite in the hypothalamus(1), but direct peripheral effects have also been observed in animal studies implicating endocannabinoids in peripheral signaling of nutritional status and lipogenesis (2). The CB 1 antagonist rimonabant (SR141716) inhibits food intake, and phase III clinical trials have shown sustained effects on weight loss in humans through effects on glucose and fat metabolism (3-5).Ghrelin is a circulating brain-gut peptide with growth hormone-releasing and appetite-inducing effects, with predominant expression in the gastric mucosa but low level widespread expression throughout the body (6 -8). Intracerebroventricular (i.c.v.) ghrelin treatment increases appetite and body weight, with a direct stimulatory effect on adipose tissue deposition demonstrated in both in vivo and in vitro studies (9, 10). It has been suggested that ghrelin favors preservation of lipid stores and the catabolism of carbohydrate-derived fuel, thereby increasing the respiratory quotient (11, 12). Ghrelin levels are high during fasting and in subjects with low body mass index, while low ghrelin levels are observed after food intake and in patients with insulin-resistant states such as type 2 diabetes, obesity, or polycystic ovarian syndrome (8). Both cannabinoids and ghrelin have been shown to have beneficial effects on the ischemic heart (13, 14). We have previously shown that ghrelin and the endocannabinoid system interact, as subanorectic doses of rimonabant can inhibit the orexigenic effect of ghrelin (15). Here we demonstrate a previously unrecognized interaction betw...

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Section: Discussionsupporting

confidence: 89%

Cannabinoids and Ghrelin Have Both Central and Peripheral Metabolic and Cardiac Effects via AMP-activated Protein Kinase

Kola

Hubina

Tucci

et al. 2005

Journal of Biological Chemistry

Self Cite

441

333

View full text Add to dashboard Cite

show abstract

“…There are many reasons for bell-shaped dose-response curves. Desensitization is one of the possibilities, especially because the ghrelin receptor is susceptible to rapid desensitization (Orkin et al, 2003;Camina et al, 2004). Another possibility is that, at higher doses of ghrelin, anorectic pathways are activated as a kind of feedback mechanism.…”

Section: Discussionmentioning

confidence: 99%

Energy Homeostasis and Gastric Emptying in Ghrelin Knockout Mice

Smet¹,

Depoortere²,

Moechars³

et al. 2005

J Pharmacol Exp Ther

103

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To elucidate the role of endogenous ghrelin in the regulation of energy homeostasis and gastric emptying, ghrelin knockout mice (ghrelin Ϫ/Ϫ ) were generated. Body weight, food intake, respiratory quotient, and heat production (indirect calorimetry), and gastric emptying ( 14 C breath test) were compared between ghrelin ϩ/ϩ and ghrelin Ϫ/Ϫ mice. In both strains, the effect of exogenous ghrelin on gastric emptying and food intake was determined. Ghrelin Ϫ/Ϫ mice showed some subtle phenotypic changes. Body weight gain and 24-h food intake were not affected, but interruption of the normal light/dark cycle triggered additional food intake in old ghrelin ϩ/ϩ but not in ghrelin Ϫ/Ϫ mice. Exogenous ghrelin increased food intake in both genotypes with a bell-shaped dose-response curve that was shifted to the left in ghrelin Ϫ/Ϫ mice. During the dark period, young ghrelin Ϫ/Ϫ mice had a lower respiratory quotient, whereas their heat production was higher than that of the wild-type littermates, inferring a leaner body composition of the ghrelin Ϫ/Ϫ mice. Absence of ghrelin did not affect gastric emptying, and the bell-shaped dose-response curves of the acceleration of gastric emptying by exogenous ghrelin were not shifted between both strains. In conclusion, ghrelin is not an essential regulator of food intake and gastric emptying, but its loss may be compensated by other redundant inputs. In old mice, meal initiation triggered by the light/dark cue may be related to ghrelin. In young animals, ghrelin seems to be involved in the selection of energy stores and in the partitioning of metabolizable energy between storage and dissipation as heat.

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“…Parallel demonstration of these opposite effects using the same experimental set up and conditions would be of considerable interest. We have shown earlier that Chinese hamster ovary (CHO) cells do not contain functional GHS receptors (38) and currently we are studying the effect of ghrelin and des-octanoyl ghrelin on the proliferation of CHO cells with and without transfection with the human GHS-R.…”

Section: Discussionmentioning

confidence: 99%

Ghrelin exerts a proliferative effect on a rat pituitary somatotroph cell line via the mitogen-activated protein kinase pathway

Nanzer

Khalaf

Mozid

et al. 2004

European Journal of Endocrinology

127

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Objectives: Ghrelin is a brain-gut peptide with GH-releasing and appetite-inducing activities and a widespread tissue distribution. Ghrelin is the endogenous ligand of the GH secretagogue receptor type 1a (GHS-R1a), and both ghrelin and the GHS-R1a are expressed in the pituitary. There are conflicting data regarding the effects of ghrelin on cell proliferation. A positive effect on proliferation and activation of the mitogen-activated protein kinase (MAPK) pathway has been found in hepatoma, adipose, cardiomyocyte and prostate cell lines. However, ghrelin has also been shown to have antiproliferative effects on breast, lung and thyroid cell lines. We therefore examined the effect of ghrelin on the rat pituitary cell line GH3. Methods: RT-PCR was used for the detection of GHS-R1a and pre-proghrelin mRNA expression in GH3 cells. The effect of ghrelin on cell proliferation was studied using [ 3 H]thymidine incorporation; cell counting and the activation of the MAPK pathway were studied using immunoblotting and inhibitors of the extracellular signal-regulated kinase 1 and 2 (ERK 1/2), protein kinase C (PKC) and tyrosine phosphatase pathways. Results: GHS-R1a and ghrelin mRNA expression were detected in GH3 cells. Ghrelin 29 M compared with control), as well as on the cell count (control 6.8 £ 10 4^8 .7 £ 10 3 cells/ml vs desoctanoyl ghrelin (10 29 M) 1.04 £ 10 5^7 .5 £ 10 3 cells/ml; P , 0.01). Ghrelin caused a significant increase in phosphorylated ERK 1/2 in immunoblotting, while desoctanoyl ghrelin showed a smaller but also significant stimulatory effect. The positive effect of ghrelin and desoctanoyl ghrelin on [ 3 H]thymidine incorporation was abolished by the MAPK kinase inhibitor U0126, the PKC inhibitor GF109203X and the tyrosine kinase inhibitor tyrphostin 23, suggesting that the ghrelin-induced cell proliferation of GH3 cells is mediated both via a PKC-MAPK-dependent pathway and via a tyrosine kinase-dependent pathway. This could also be clearly demonstrated by Western blot analysis, where a transient increase in ERK 1/2 phosphorylation by ghrelin was attenuated by all three inhibitors. Conclusion: We have shown a novel role for ghrelin in stimulating the proliferation of a somatotroph pituitary tumour cell line, suggesting that ERK activation is involved in mediating the effects of ghrelin on cell proliferation. Desoctanoyl ghrelin showed a similar effect. As ghrelin has been shown to be expressed in both normal and adenomatous pituitary tissue, locally produced ghrelin may play a role in pituitary tumorigenesis via an autocrine/paracrine pathway.European Journal of Endocrinology 151 233-240

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Rapid desensitisation of the GH secretagogue (ghrelin) receptor to hexarelin in vitro

Cited by 20 publications

References 34 publications

Cannabinoids and Ghrelin Have Both Central and Peripheral Metabolic and Cardiac Effects via AMP-activated Protein Kinase

Cannabinoids and Ghrelin Have Both Central and Peripheral Metabolic and Cardiac Effects via AMP-activated Protein Kinase

Energy Homeostasis and Gastric Emptying in Ghrelin Knockout Mice

Ghrelin exerts a proliferative effect on a rat pituitary somatotroph cell line via the mitogen-activated protein kinase pathway

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