Disease relevance of GHRL

• Recently, a polymorphism (Arg-51-Gln) within the ghrelin gene (GHRL) was described to be associated with obesity [1].
• Among genotyped GHRL SNPs, the variant allele for GHRL -4427G>A was inversely associated with all NHL [odds ratios (OR), 0.78; 95% confidence interval (95% CI), 0.59-1.0] and more specifically with diffuse large cell lymphoma (DLCL; homozygous variant: OR, 0.31; 95% CI, 0.13-0.74) [2].
• This review highlights the evidence for the expression, regulation and potential functional role of ghrelin and its receptor in hormone-dependent cancers, such as prostate and breast cancer [3].
• Ghrelin, a growth hormone-releasing hormone produced by gastroenteropancreatic endocrine cells, hypothalamus, and pituitary, was recently identified in medullary thyroid carcinomas and derived cell lines [4].
• Ghrelin and the growth hormone secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility [5].
• Obesity could alter circulating ghrelin profile, and relative A-Ghr excess could contribute to obesity-associated insulin resistance in metabolic syndrome [6].
• Our study demonstrates that ghrelin secretion is negatively affected by autoimmune gastritis, and its serum level represents the most sensitive and specific noninvasive marker for selecting patients at high risk for ABG [7].

Psychiatry related information on GHRL

• DESIGN: We genotyped 856 Amish samples for three missense polymorphisms in GHRL, Arg51Gln, Leu72Met (rs696217), and Gln90Leu (rs4684677) and performed association analyses with eating behavior traits and metabolic syndrome as defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines [8].
• Ghrelin is unlikely to play a causal role in anorexia nervosa or obesity [9].
• We showed recently that ghrelin promotes slow-wave sleep and the nocturnal release of GH, cortisol and prolactin in humans [10].
• Therefore, we studied the effect of sleep deprivation on nocturnal ghrelin secretion [11].
• Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, has been shown to promote slow-wave sleep (SWS, non-REM sleep stages 3 and 4) [11].

High impact information on GHRL

• Taking into account all these activities, ghrelin plays important roles for maintaining GH release and energy homeostasis in vertebrates [12].
• In addition, ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, a region known to control food intake [12].
• Ghrelin is orexigenic; it is secreted from the stomach and circulates in the bloodstream under fasting conditions, indicating that it transmits a hunger signal from the periphery to the central nervous system [12].
• Elevated plasma ghrelin levels in Prader Willi syndrome [13].
• Antibodies and antagonists of NPY and AGRP abolished ghrelin-induced feeding [14].

Chemical compound and disease context of GHRL

• On the other hand, in obesity ghrelin shows preserved influence on PRL, ACTH, and insulin secretion as well as in glucose levels [15].
• Similar to what has been reported for ghrelin administration, our subjects ate 35.9 +/- 10.9% more when infused with GHRP-2 vs. saline, with every subject increasing their intake even when calculated per kg body weight (136.0 +/- 13.0 kJ/kg [32.5 +/- 3.1 kcal/kg] vs. 101.3 +/- 10.5 kJ/kg [24.2 +/- 2.5 kcal/kg], p = 0.008) [16].
• Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans [10].
• Using pertussis toxin and the phospholipase C inhibitor U-73122, we show that ghrelin signals through the Gq pathway in the RC-4B/C.40 cells [17].
• While oestrogen, progesterone and growth factors, including growth hormone (GH), are clearly implicated in the pathogenesis of breast cancer, there is now evidence that the newly described ghrelin axis is also involved [18].

Biological context of GHRL

• We screened the GHRL coding region in 215 extremely obese German Children and adolescents (study group 1) and 93 normal weight students (study group 2) by single strand conformation polymorphism analysis (SSCP) [1].
• Alternative splicing of the ghrelin gene transcript can result in the translation of a second biologically active peptide, des-Gln14-ghrelin [19].
• Ghrelin plays a key role in the regulation of growth hormone secretion and energy homeostasis [20].
• Originally thought of as a stomach-derived endocrine peptide acting via its receptors in the central nervous system to stimulate food intake and growth hormone expression, ghrelin and its receptor (growth hormone secretagogue receptor (GHS-R)) are widely expressed in a number of organ systems, including cancer cells [5].
• We also analyzed the effects of ghrelin on cell proliferation in N-PAP and ARO thyroid carcinoma cell lines [4].

Anatomical context of GHRL

• Moreover, ghrelin induced dose-dependent inhibition of growth in cell lines [4].
• Strong ghrelin immunoreactivity was found in fetal but not in infant or adult thyroids [4].
• However, the direct functional role of ghrelin and its receptor in tumors of central nervous system origin remains to be defined [5].
• The acylated form of ghrelin acts as a ligand for the growth hormone secretagogue receptor and can stimulate the release of growth hormone from the pituitary gland [21].
• Ghrelin is involved in the regulation of GH release, but it has recently been suggested that ghrelin may have other actions, including effects on appetite, carbohydrate metabolism, heart, kidney, pancreas, gonads, and cell proliferation [22].

Associations of GHRL with chemical compounds

• Ghrelin is a GH-releasing peptide that also has an important role as an orexigenic hormone-stimulating food intake [23].
• Ghrelin and a number of the known nonpeptide GH secretagogues acted as agonists stimulating inositol phosphate turnover further [23].
• Blood samples for ghrelin, insulin, and glucose were taken at time -30, 0, 15, 30, 45, 60, 120 min during both tests [24].
• GH levels were assayed at each time point in all sessions; PRL, ACTH, cortisol, and aldosterone levels were also assayed after administration of ghrelin and/or HEX [25].
• CONCLUSIONS: Assuming that l-arginine reduces somatostatin outflow, we infer that ghrelin can activate hypothalamo-pituitary pathways that are both dependent upon and independent of somatostatinergic restraint even in the face of a strong stress-related signal [26].
• We measured ghrelin, GH, ACTH, cortisol, glucose, free fatty acids, TNF-alpha, IL-6, and IL-1 receptor antagonist [27].

Physical interactions of GHRL

• Ghrelin-binding sites were investigated using reverse transcriptase-polymerase chain reaction to detect its growth hormone secretagogue receptor (GHS-R) mRNA and an in situ-binding localization procedure [4].
• The discovery of ghrelin adds a new component to the complex machinery responsible for regulation of GH secretion in connection with the regulation of appetite and energy homeostasis [28].
• The present results also show that Ghrelin interacts with GHRH and SS to in the release of GH from porcine adenohypophysial cells [29].
• Absence of BBB permeation by obestatin and adiponectin was in contrast to the saturable transport of human ghrelin reported previously [30].
• Effects of the IGF-I/IGFBP-3 complex on GH and ghrelin nocturnal concentrations in low birth weight children [31].

Regulatory relationships of GHRL

• In conclusion, our results demonstrate that the ovarian surface epithelium and related tumors are potential targets for systemic or locally produced ghrelin because they express the functional type 1a GHS-R [32].
• In conclusion, this study clearly demonstrates that ghrelin stimulates SS and PP release in man [33].
• Both SRIF and CST similarly inhibited (p < 0.01) circulating ghrelin levels of about 55% [34].
• Ghrelin is an orexigenic hormone that induces NPY release and inhibits proinflammatory cytokines via its antagonistic relationship with leptin [2].
• In conclusion, ghrelin-induced GH secretion was severely blunted in patients with active Cushing's syndrome, in addition to a remarkable hyper-response in ACTH and cortisol secretion [35].

Other interactions of GHRL

• We studied five lean and five obese young men [ages: 24.2 +/- 1.0 (lean) and 21.8 +/- 1.6 (obese) years (difference not significant); body mass indexes: 35.0 +/- 1.3 and 23.0 +/- 0.3 kg/m2 (P = 0.01)], sampled blood every 7 min over 24 h, and measured ghrelin, adiponectin, and leptin in 2,070 samples for a total of 6,210 data points [20].
• Together, these findings suggest a novel role for the ghrelin/GHS-R axis in astrocytoma cell migration and invasiveness of cancers of central nervous system origin [5].
• Ghrelin can bind to a species of high density lipoprotein associated with paraoxonase [21].
• PYY, ghrelin, GIP, insulin, and glucose concentrations and four markers of satiety were measured for 240 min after a mixed meal [9].
• To clarify the mechanisms of action underlying the GH-releasing activity of ghrelin in humans, its interaction with GHRH and HEX was also studied [25].
• An additive effect of high leptin and low ghrelin on metabolic disturbances was observed: low ghrelin concentration (adjusted for age and sex) (P < 0.001) was associated with the MS and type 2 diabetes in the highest but not in the lower leptin quartiles [36].

Analytical, diagnostic and therapeutic context of GHRL

• We analyzed ghrelin expression by immunohistochemistry, in situ hybridization, and reverse transcriptase-polymerase chain reaction in 15 fetal, 4 infant, and 10 adult thyroids, and in 54 tumors of follicular origin [4].
• Plasma levels of immunoreactive ghrelin after total gastrectomy in three patients were reduced to approximately half of their pre-gastrectomy values, after which they gradually increased [37].
• Human ghrelin was purified from the stomach by gel filtration and high performance liquid chromatography, using a ghrelin-specific radioimmunoassay and an intracellular calcium influx assay on a stable cell line expressing GHS-R to test the fractions [37].
• An endogenous species of ghrelin is found to co-purify with high density lipoprotein during density gradient centrifugation and subsequent gel filtration [21].
• The ligation of GHS-R by ghrelin on these cells resulted in an increase in intracellular calcium mobilization, protein kinase C activation, actin polymerization, matrix metalloproteinase-2 activity, and astrocytoma motility [5].

References