Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a

Casanueva, Felipe F.; Camiña, Jesús P.; Carreira, Marcos C.; Pazos, Yolanda; Varga, József; Schally, Andrew V.

doi:10.1073/pnas.0811680106

Cited by 55 publications

(21 citation statements)

References 44 publications

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“…In this sense, it has been suggested that GOAT is located in the membrane of the ER and mediates the translocation of the octanoyl-CoA from the cytosolic side to the ER lumen prior to the transport of acylated ghrelin to the Golgi [31][32][33]. The subcellular localisation of ghrelin and GOAT found in the present study is similar to that observed in human myometrial smooth muscle cells and in the human embryonic kidney (HEK) 293 cell line [9,[34][35][36]. Further investigation is warranted to ascertain the mechanisms of ghrelin trafficking in human adipocytes.…”

Section: Discussionsupporting

confidence: 86%

The ghrelin O-acyltransferase–ghrelin system reduces TNF-α-induced apoptosis and autophagy in human visceral adipocytes

et al. 2012

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Aims/hypothesis Proinflammatory and proapoptotic cytokines such as TNF-α are upregulated in human obesity. We evaluated the association between ghrelin isoforms (acylated and desacyl ghrelin) and TNF-α in obesity and obesity-associated type 2 diabetes, as well as the potential role of ghrelin in the control of apoptosis and autophagy in human adipocytes. Methods Plasma concentrations of the ghrelin isoforms and TNF-α were measured in 194 participants. Ghrelin and ghrelin O-acyltransferase (GOAT) levels were analysed by western-blot, immunohistochemistry and real-time PCR in 53 biopsies of human omental adipose tissue. We also determined the effect of acylated and desacyl ghrelin (10 to 1,000 pmol/l) on TNF-α-induced apoptosis and autophagy-related molecules in omental adipocytes. Results Circulating concentrations of acylated ghrelin and TNF-α were increased, whereas desacyl ghrelin levels were decreased in obesity-associated type 2 diabetes. Ghrelin and GOAT were produced in omental and subcutaneous adipose tissue. Visceral adipose tissue from obese patients with type 2 diabetes showed higher levels of GOAT, increased adipocyte apoptosis and increased expression of the autophagyrelated genes ATG5, BECN1 and ATG7. In differentiating Diabetologia (2012) human omental adipocytes, incubation with acylated and desacyl ghrelin reduced TNF-α-induced activation of caspase-8 and caspase-3, and cell death. In addition, acylated ghrelin reduced the basal expression of the autophagyrelated genes ATG5 and ATG7, while desacyl ghrelin inhibited the TNF-α-induced increase of ATG5, BECN1 and ATG7 expression. Conclusions/interpretation Apoptosis and autophagy are upregulated in human visceral adipose tissue of patients with type 2 diabetes. Acylated and desacyl ghrelin reduce TNF-α-induced apoptosis and autophagy in human visceral adipocytes.

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Section: Discussionsupporting

confidence: 86%

The ghrelin O-acyltransferase–ghrelin system reduces TNF-α-induced apoptosis and autophagy in human visceral adipocytes

et al. 2012

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“…GH synthesis and secretion are induced by hypothalamic GHRH and gut-derived ghrelin. GHRH may also act as a coagonist for the ghrelin receptor (28). Hypothalamic SRIF suppresses GH secretion mainly by highaffinity binding to SSTR2 and SSTR5 receptor subtypes expressed on somatotrophs (90).…”

Section: Figurementioning

confidence: 99%

Acromegaly pathogenesis and treatment

Melmed¹

2009

J. Clin. Invest.

608

472

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Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly -a disorder of disproportionate skeletal, tissue, and organ growth. High GH and IGF1 levels lead to comorbidities including arthritis, facial changes, prognathism, and glucose intolerance. If the condition is untreated, enhanced mortality due to cardiovascular, cerebrovascular, and pulmonary dysfunction is associated with a 30% decrease in life span. This Review discusses acromegaly pathogenesis and management options. The latter include surgery, radiation, and use of novel medications. Somatostatin receptor (SSTR) ligands inhibit GH release, control tumor growth, and attenuate peripheral GH action, while GH receptor antagonists block GH action and effectively lower IGF1 levels. Novel peptides, including SSTR ligands, exhibiting polyreceptor subtype affinities and chimeric dopaminergic-somatostatinergic properties are currently in clinical trials. Effective control of GH and IGF1 hypersecretion and ablation or stabilization of the pituitary tumor mass lead to improved comorbidities and lowering of mortality rates for this hormonal disorder.

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“…Just recently, interactions between the ghrelin and the GHRH-signaling pathway have been observed. Casanueva et al (2008) reported that the ghrelin GHS-R1a receptor can be activated by GHRH. Moreover, they discovered that GHRH appears to be an allosteric enhancer of ghrelin action.…”

Section: Ghrelin Effectsmentioning

confidence: 99%

Interactions of ghrelin signaling pathways with the GH neuroendocrine axis: a new and experimentally tested model

Wagner¹,

Caplan²,

Tannenbaum³

2009

Journal of Molecular Endocrinology

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Growth hormone (GH) is secreted in a pulsatile fashion from the pituitary gland into the circulation. Release is governed by two hypothalamic neuropeptides, growth hormone-releasing hormone (GHRH) and somatostatin (SRIF), resulting in secretion episodes with a periodicity of 3 . 3 h in the male rat. Ghrelin is an additional recently identified potent GH-secretagogue. However, its in vivo interactions with the GH neuroendocrine axis remain to be elucidated. Moreover, two different sites of ghrelin synthesis are involved, the stomach and the hypothalamus. We used our previously developed core model of GH oscillations and added the sites of ghrelin action at the pituitary and in the hypothalamus. With this extended model, we simulated the effects of central and peripheral ghrelin injections, monitored the GH profile and compared it with existing experimental results. Systemically administered ghrelin elicits a GH pulse independent of SRIF, but only in the presence of GHRH. The peripheral ghrelin signal is mediated to the brain via the vagus nerve, where it augments the release of GHRH and stimulates the secretion of neuropeptide-Y (NPY). By contrast, centrally administered ghrelin initiates a GH pulse by increasing the GHRH level and by antagonizing the SRIF block at the pituitary. In addition, NPY neurons are activated, which trigger a delayed SRIF surge. The major novel features of the present model are a) the role played by NPY, and b) the dissimilar functions of ghrelin in the hypothalamus and at the pituitary. Furthermore, the predictions of the model were experimentally examined and confirmed.

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Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a

Cited by 55 publications

References 44 publications

The ghrelin O-acyltransferase–ghrelin system reduces TNF-α-induced apoptosis and autophagy in human visceral adipocytes

The ghrelin O-acyltransferase–ghrelin system reduces TNF-α-induced apoptosis and autophagy in human visceral adipocytes

Acromegaly pathogenesis and treatment

Interactions of ghrelin signaling pathways with the GH neuroendocrine axis: a new and experimentally tested model

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