Hypothalamic Growth Hormone Secretagogue-Receptor (GHS-R) Expression Is Regulated by Growth Hormone in the Rat

Bennett, Pamela A.; Thomas, Graham H.; Howard, Andrew D.; Feighner, Scott D.; Ploeg, Lex H.T. Van der; Smith, Roy G.; Robinson, Iain C. A. F.

doi:10.1210/endo.138.11.5476

Cited by 156 publications

(77 citation statements)

References 53 publications

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“…Indeed, pituitary and hypothalamic GHS-R mRNA levels are inhibited by GH (36,42), whereas pituitary GHS-R expression is up-regulated by GH-releasing hormone (GHRH) (43). Additional heterologous signals involved in the regulation of GHS-R expression are sex steroids (44) and, notably, glucocorticoids (26).…”

Section: Discussionmentioning

confidence: 99%

Expression and homologous regulation of GH secretagogue receptor mRNA in rat adrenal gland

Barreiro

Pinilla²,

Aguilar³

et al. 2002

European Journal of Endocrinology

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Objective: GH secretagogues (GHSs) elicit a variety of biological effects in several endocrine and nonendocrine target tissues, including activation of the hypothalamic -pituitary-adrenal axis. The latter is mainly carried out through a central hypothalamic action; yet the possibility of additional effects directly at the adrenal level cannot be ruled out. The aims of this study were to evaluate the expression and homologous regulation of the GHS-receptor (GHS-R) gene in rat adrenal and to assess the effects of synthetic (GH releasing peptide-6 -GHRP-6) and natural (ghrelin) ligands of GHS-R upon basal and ACTH-stimulated corticosterone secretion in vitro. Design and Methods: Analysis of adrenal expression of target mRNAs (GHS-R, GHS-R1a, ghrelin, and several steroidogenic factors) was conducted by means of primer-specific, semi-quantitative RT-PCR. Evaluation of corticosterone secretion by incubated adrenal tissue was carried out by specific RIA. Results: RT-PCR analysis demonstrated expression of the GHS-R gene, but not of the gene encoding the cognate ligand ghrelin, in rat adrenal. Moreover, expression of the mRNA coding for the type 1a GHS-R (GHS-R1a), i.e. the biologically active receptor form, was demonstrated. The adrenal expression of the GHS-R message appeared under the regulation of homologous signals in vitro, as short-term incubation of adrenal samples in serum-free medium induced a significant increase in GHS-R mRNA levels that was inhibited by exposure to different doses of GHRP-6 (10 29 -10 25 mol/l) or ghrelin (10 27 mol/l). Notably, an opposite pattern of homologous regulation of GHS-R gene expression was observed at the pituitary. Finally, short-term stimulation with increasing concentrations of GHRP-6 (10 29 -10 25 mol/l) or ghrelin (10 27 mol/l) failed to alter basal and ACTHstimulated corticosterone secretion in vitro, neither did it modify ACTH-stimulated mRNA expression levels of several upstream elements in the steroidogenic route: the steroidogenic acute regulatory (StAR) protein, and the enzymes P450 cholesterol side-chain cleavage (P450scc) and 3b-hydroxysteroid dehydrogenase (3b-HSD). Conclusions: Our study provides novel evidence for the expression and homologous regulation of the GHS-R gene in rat adrenal. However, our results cast doubts on the possibility of direct adrenal actions of ligands of the GHS-R in the regulation of corticosterone secretion in the rat.

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Section: Discussionmentioning

confidence: 99%

Expression and homologous regulation of GH secretagogue receptor mRNA in rat adrenal gland

Barreiro

Pinilla²,

Aguilar³

et al. 2002

European Journal of Endocrinology

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“…The cloned GHS receptor 1A is present in the hypothalamic paraventricular nucleus (PVN) (30,31) where the corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) neurons that regulate corticosterone release are localised (32). Since ghrelin stimulated the release of both CRH and AVP from hypothalamic explants (33), it is possible that GHS activates these neurons directly to mediate the effects on the HPA axis.…”

Section: Inguinalmentioning

confidence: 99%

Glucocorticoid-dependent stimulation of adiposity and appetite by a ghrelin mimetic in the rat

Tung

Hewson

Dickson

2004

European Journal of Endocrinology

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Objective: Chronic administration of GH secretagogues (GHSs) induces a state of positive energy balance in rodents by a GH-independent mechanism. Here we sought to determine to what extent the GHS effects to increase food intake and increase fat accumulation are glucocorticoid-dependent. Design: The effects of twice-daily s.c. injections of GH-releasing peptide-6 (GHRP-6) (250 mg/kg) for 2 weeks on body weight, food intake and fat pad weight were determined in both adrenalectomised (ADX) rats (with or without basal corticosterone replacement) and adrenal-intact rats. Results: All GHS-injected rats had a significantly increased body weight at the end of 2 weeks of treatment compared with saline controls. However, increased fat accumulation was only seen in adrenalintact rats, with a 15% increase in s.c. inguinal (P , 0.05 vs saline controls) and 20% increase in visceral mesenteric (P , 0.05) fat pad weights following GHS treatment. The increased body weight observed in ADX rats following GHS treatment was not due to increased fat mass or increased weight of other organs measured. Food intake was increased for up to 7 h following a single injection of GHRP-6 in both the adrenal-intact (P , 0.01) and corticosterone-replacement groups (P , 0.05). This stimulating effect on food intake was not observed at any time point in the ADX rats without corticosterone replacement. Conclusion: These data suggest that GHS-induced body weight gain is glucocorticoid-independent. However, basal levels of glucocorticoids are permissive for the GHS-induced increase in food intake whilst activation of the hypothalamo -pituitary-adrenal axis appears to contribute to the GHSinduced accumulation of fat mass. European Journal of Endocrinology 150 905-911

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“…For example, ghrelin modulates the activity of neuropeptide Y and melanocortin neurons in exerting a potent orexigenic effect (4)(5)(6)(7). The colocalization of the growth hormone secretagogue 1 receptor (GHSR; the only known receptor for ghrelin) with these hypothalamic neurons further indicates that the hypothalamus is a main target site for ghrelin (8)(9)(10). Interestingly, the presence of the transcripts encoding the GHSR message has been detected in various extrahypothalamic brain regions as well, including the ventral tegmental area (VTA) (11,12).…”

Section: Introductionmentioning

confidence: 99%

Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite

et al. 2006

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The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin-and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding.

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Hypothalamic Growth Hormone Secretagogue-Receptor (GHS-R) Expression Is Regulated by Growth Hormone in the Rat

Cited by 156 publications

References 53 publications

Expression and homologous regulation of GH secretagogue receptor mRNA in rat adrenal gland

Expression and homologous regulation of GH secretagogue receptor mRNA in rat adrenal gland

Glucocorticoid-dependent stimulation of adiposity and appetite by a ghrelin mimetic in the rat

Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite

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