Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: GHRL
Cytogenetic location: 3p25.3 Genomic coordinates (GRCh38) : 3:10,285,666-10,292,947 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p25.3 | {Obesity, susceptibility to} | 601665 | Autosomal dominant; Autosomal recessive; Multifactorial | 3 |
Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHSR; 601898) and is involved in regulating growth hormone (GH; 139250) release. Ghrelin is derived from a preprohormone called preproghrelin, which also generates a second peptide called obestatin (Zhang et al., 2005).
Small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone from the pituitary. They act through the growth hormone secretagogue receptor, a G protein-coupled receptor. Kojima et al. (1999) reported the purification and identification in rat stomach of an endogenous ligand specific for GHSR. The purified ligand is a peptide of 28 amino acids in which the serine-3 residue is n-octanoylated. The acylated peptide specifically releases GH both in vivo and in vitro, and O-n-octanoylation at serine-3 is essential for the activity. Kojima et al. (1999) designated the GH-releasing peptide 'ghrelin' ('ghre' is the Proto-Indo-European root of the word 'grow'). Human ghrelin is homologous to rat ghrelin apart from 2 amino acids. The occurrence of ghrelin in both rat and human indicates that GH release from the pituitary may be regulated not only by hypothalamic growth hormone-releasing hormone (GHRH; 139190), but also by ghrelin. Human preproghrelin, isolated from a stomach cDNA library, consists of 117 amino acids. Rat and human preproghrelins are 82.9% identical. Northern blot analysis of rat tissues showed that preproghrelin mRNA of 0.62 kb occurs in stomach. In situ hybridization indicated that ghrelin mRNA is found in the region from the neck to the base of the oxyntic gland. Ghrelin-immunoreactive cells in the stomach have the same distribution as that found using in situ hybridization. The distribution pattern and morphologic features of the labeled and immunostained cells showed that ghrelin cells are endocrine cells.
Kojima et al. (1999) detected a ghrelin transcript in brain by RT-PCR amplification but not by Northern blot analysis. Immunohistochemical analyses performed after colchicine treatment revealed that ghrelin-immunoreactive neurons were localized in the hypothalamic arcuate nucleus.
Tanaka et al. (2001) cloned a splice variant of mouse ghrelin, which they called ghrelin gene-derived transcript (GGDT), from adult mouse testis. The variant encodes a deduced 54-amino acid peptide generated by alternative exon 1 usage and alternative splicing. Northern blot analysis showed that GGDT expression is limited to the mouse testis and is developmentally regulated, being absent in testis at 2 weeks of age and increasing to reach adult expression levels at 4 weeks of age. Tanaka et al. (2001) found no significant change in the abundance of full-length ghrelin mRNA in the stomach from 2 to 8 weeks of age.
Using RT-PCR, RACE, and in silico analyses, Seim et al. (2007) identified several GHRL splice variants in human tissues and cell lines. Some variants do not encode ghrelin, but instead encode the C-terminal region of preproghrelin, including the obestatin sequence, and 1 variant encodes obestatin only. Splice variants differing in their 5-prime UTRs were also identified. In addition, Seim et al. (2007) identified noncoding transcripts originating from GHRLOS (618445), a gene on the opposite strand of GHRL.
Obestatin
Zhang et al. (2005) searched for orthologs of the human ghrelin gene and compared preproghrelin sequences from 11 mammalian species. In addition to the known ghrelin mature peptide, which immediately follows the signal peptide, they identified another conserved region that was flanked by potential convertase cleavage sites. This region encoded a putative 23-amino acid peptide with a flanking conserved glycine residue at the C terminus, suggesting that it might be amidated. Zhang et al. (2005) named this ghrelin-associated peptide obestatin, from the Latin 'obedere,' to devour, and 'statin,' denoting suppression.
Seim et al. (2007) determined that the GHRL gene contains 6 exons and spans 7.2 kb.
Scott (2000) mapped the human gene encoding ghrelin to 3p26-p25 based on sequence similarity between the ghrelin precursor (GenBank AB029434) and a BAC (GenBank AC008116) mapped to 3p26-p25.
Gross (2019) mapped the GHRL gene to chromosome 3p25.3 based on an alignment of the GHRL sequence (GenBank AF296558) with the genomic sequence (GRCh38).
Kojima et al. (1999) found that ghrelin circulates in healthy human blood at a considerable plasma concentration (117.2 +/- 37.2 fmol/ml(-1); n = 6); this, together with the finding that ghrelin, when injected intravenously, induces GH release, suggested to the authors that this molecule is produced in and secreted from the stomach, circulating in the bloodstream to act on the pituitary.
Takaya et al. (2000) studied GH-releasing activity and other effects generated by ghrelin in 4 normal men aged 28 to 37 years. They demonstrated that ghrelin strongly stimulates GH release in humans in a dose-dependent manner. Per mol, ghrelin is more potent for GH release than GHRH. The lowest dose of ghrelin used (0.2 microg/kg) led to massive GH release (43.3 +/- 6.0 ng/mL), with minimum effects on ACTH or PRL (176760). Ghrelin administration did not change serum LH (see 118850), FSH (136530), or TSH (188540) levels.
Kluge et al. (2007) investigated the effect of pulsatile ghrelin administration on the nocturnal secretion patterns of LH and testosterone in 10 healthy young men. They found that ghrelin caused both a delay and suppression of the amplitude of LH pulses. They concluded that, as in nonhuman mammals, ghrelin may affect the hypothalamic-pituitary-gonadal axis predominantly by suppressing secretion of LH.
Tschop et al. (2000) showed that peripheral daily administration of ghrelin caused weight gain by reducing fat utilization in mice and rats. Intracerebroventricular administration of ghrelin generated a dose-dependent increase in food intake and body weight. Rat serum ghrelin concentrations were increased by fasting and were reduced by refeeding or oral glucose administration, but not by water ingestion. Tschop et al. (2000) proposed that ghrelin, in addition to its role in regulating GH secretion, signals the hypothalamus when an increase in metabolic efficiency is necessary.
Nakazato et al. (2001) demonstrated that ghrelin is involved in the hypothalamic regulation of energy homeostasis. Intracerebroventricular injections of ghrelin strongly stimulated feeding in rats and increased body weight gain. Ghrelin also increased feeding in rats that were genetically deficient in growth hormone. Antighrelin immunoglobulin G robustly suppressed feeding. After intracerebroventricular ghrelin administration, FOS protein (164810), a marker of neuronal activation, was found in regions of primary importance in the regulation of feeding, including neuropeptide Y (NPY; 162640) neurons and agouti-related protein (AGRP; 602311) neurons. Antibodies and antagonists of NPY and AGRP abolished ghrelin-induced feeding. Ghrelin augmented NPY gene expression and blocked leptin (LEP; 164160)-induced feeding reduction, implying that there is a competitive interaction between ghrelin and leptin in feeding regulation. Nakazato et al. (2001) concluded that ghrelin is a physiologic mediator of feeding and probably has a function in growth regulation by stimulating feeding and release of growth hormone.
Date et al. (2001) demonstrated a role for ghrelin in the central regulation of gastric function. Specifically, intracerebroventricular administration of ghrelin stimulated gastric acid secretion in a dose-dependent and atropine-sensitive manner. Vagotomy abolished gastric acid secretion. Immunohistochemistry demonstrated the induction of Fos expression in the nucleus of the solitary tract and dorsomotor nucleus of the rat vagus nerve.
Cummings et al. (2002) investigated plasma ghrelin levels after weight loss induced by diet or by gastric bypass surgery. They reasoned that if circulating ghrelin participates in the adaptive response to weight loss, its levels should rise with dieting. Because ghrelin is produced primarily in the stomach, weight loss after gastric bypass surgery might be accompanied by impaired ghrelin secretion. They found an increase in the plasma ghrelin level with diet-induced weight loss. Gastric bypass was associated with markedly suppressed ghrelin levels, possibly contributing to the weight-reducing effect of the procedure.
Leonetti et al. (2003) observed a significant difference in plasma ghrelin levels between laparoscopic Roux-en-Y gastric bypass (LRYGBP) and laparoscopic adjustable silicone gastric banding (LASGB), suggesting that each procedure could induce weight loss by a different mechanism in which ghrelin could be involved.
Kojima et al. (2001) reviewed the role of ghrelin. This peptide is found in the secretory granules of X/A-like cells, a distinct endocrine cell type found in the submucosal layer of the stomach (Date et al., 2000). These cells contain round, compact, electron-dense granules and are filled with ghrelin. Ghrelin immunoreactive cells are also found in the small and large intestines.
Cowley et al. (2003) discovered expression of ghrelin in a theretofore uncharacterized group of neurons adjacent to the third ventricle between the dorsal, ventral, paraventricular, and arcuate hypothalamic nuclei. These neurons send efferents onto key hypothalamic circuits, including those producing NPY, AGRP, proopiomelanocortin (POMC; 176830) products, and corticotropin-releasing hormone (CRH; 122560). Within the hypothalamus, ghrelin bound mostly on presynaptic terminals of NPY neurons. Using electrophysiologic recordings, Cowley et al. (2003) found that ghrelin stimulated the activity of arcuate NPY neurons and mimicked the effect of NPY in the paraventricular nucleus of the hypothalamus. Cowley et al. (2003) proposed that at these sites, release of ghrelin may stimulate the release of orexigenic peptides and neurotransmitters, thus representing a novel regulatory circuit controlling energy homeostasis.
Abizaid et al. (2006) demonstrated that ghrelin bound to neurons of the ventral tegmental area (VTA) in mice and rats, 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 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.
Dixit et al. (2004) demonstrated that ghrelin and its receptor, GHSR, are expressed in human T lymphocytes and monocytes, where ghrelin acts via GHSR to inhibit specifically the expression of proinflammatory anorectic cytokines such as IL1-beta (147720), IL6 (147620), and TNF-alpha (191160). Ghrelin led to a dose-dependent inhibition of leptin-induced cytokine expression, whereas leptin upregulated GHSR expression on human T lymphocytes. Dixit et al. (2004) proposed the existence of a reciprocal regulatory network by which ghrelin and leptin control immune cell activation and inflammation. In a murine model of endotoxemia, Dixit et al. (2004) also showed that ghrelin has potent antiinflammatory effects and attenuates endotoxin-induced anorexia.
Pagotto et al. (2003) investigated circulating ghrelin levels in a group of hypogonadal men before and after therapeutic intervention aiming at normalization of low testosterone concentrations. After the 6-month replacement testosterone therapy, ghrelin levels of hypogonadal patients increased and did not differ significantly in comparison with both control groups. The positive correlation between ghrelin and androgens still persisted after testosterone replacement therapy, after adjusting for confounding variables. The authors concluded that androgens modulate circulating ghrelin concentrations in humans.
Farquhar et al. (2003) measured ghrelin in neonates who were small (SGA), appropriate (AGA), or large (LGA) for gestational age and observed that ghrelin concentration was 40% higher in SGA neonates compared with AGA and LGA neonates. There was a positive correlation between ghrelin and gestational age in AGA/LGA and a negative correlation in SGA neonates. The authors suggested that ghrelin may play a physiologic role in fetal adaptation to intrauterine malnutrition.
To determine whether ghrelin releases GH by a pituitary or a hypothalamic action, Popovic et al. (2003) compared a group of patients with organic lesions mainly in the hypothalamic area with matched controls. Patients showed a severe GH deficiency after hypothalamic stimulation by insulin tolerance test, but partial response after GHRH (139190) administration. The authors concluded that when hypothalamic structures are not operative, ghrelin, either alone or in combination with GHRH, is not able to significantly release GH. The authors postulated a hypothalamic point of action for ghrelin-induced GH secretion.
The studies of Corbetta et al. (2003) suggested that carcinoids and pancreatic tumors rarely cause ghrelin hypersecretion. However, in this series, 1 pancreatic ghrelinoma not associated with clinical features of acromegaly was identified.
After administration of ghrelin, Doi et al. (2006) observed increases in Ia2-beta (PTPRN2; 601698) in mouse brain, pancreas, and insulinoma cell lines, but not Ia2 (PTPRN; 601773). Administration of ghrelin or overexpression of Ia2-beta inhibited glucose-stimulated insulin secretion in insulinoma cells, and inhibition of Ia2-beta overexpression by RNA interference ameliorated ghrelin's inhibitory effects on glucose-stimulated insulin secretion. Doi et al. (2006) suggested that the inhibitory effects of ghrelin on glucose-stimulated insulin secretion are at least partly due to increased expression of Ia2-beta induced by ghrelin.
Leidy et al. (2004) studied the effects of a 3-month energy deficit-imposing diet and exercise intervention on circulating ghrelin in healthy women of normal weight. Ghrelin significantly increased over time in the weight-loss group compared with the controls and the weight-stable group (P less than 0.05). Changes in ghrelin were negatively correlated with changes in body weight (r = -0.61; P less than 0.05). Body fat, body weight, and resting metabolic rate significantly decreased in the weight-loss group before the increase in ghrelin. The authors concluded that ghrelin responds in a compensatory manner to changes in energy homeostasis in healthy young women, and that ghrelin exhibits particular sensitivity to changes in body weight.
Yang et al. (2008) found that mouse Goat (MBOAT4; 611940) octanoylated ghrelin following cotransfection of Goat and preproghrelin in cultured endocrine cell lines. Mutation analysis showed that Goat octanoylated ghrelin on ser3, a modification required for its endocrine effects.
Checchi et al. (2007) studied the diagnostic use of the measurement of serum ghrelin compared with other markers of gastric damage in predicting the presence of atrophic body gastritis (ABG) in patients with autoimmune gastritis. All 233 patients with autoimmune gastritis and 211 control subjects were screened for circulating parietal cell antibodies (PCAs) and were tested for serum ghrelin, gastrin (137250), pepsinogen I (see 169700) and II (169740), and anti-Helicobacter pylori antibody levels. A total of 52 patients and 28 control subjects underwent a gastric endoscopy. In PCA/positive patients, mean serum ghrelin levels were significantly lower, and mean serum gastrin levels were significantly higher with respect to PCA/negative patients. Checchi et al. (2007) concluded 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.
Andrews et al. (2008) showed that ghrelin initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein-2 (UCP2; 601693). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY (162640)/AgRP (602311) neurons, for ghrelin-triggered synaptic plasticity of proopiomelanocortin (POMC; 176830)-expressing neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK (see 602739), CPT1 (600528), and free radicals that are scavenged by UCP2. Andrews et al. (2008) concluded that their results revealed a signaling modality connecting mitochondria-mediated effects of G protein-coupled receptors on neuronal function and associated behavior.
In studies in mice lacking Mboat4 and mice overexpressing Mboat4, Kirchner et al. (2009) demonstrated that Mboat4 is regulated by nutrient availability, depends on specific dietary lipids as acylation substrates, and links ingested lipids to energy expenditure and body fat mass. Kirchner et al. (2009) concluded that ghrelin acylation and the secretion of acylated ghrelin probably represent 2 independent processes, and that the ghrelin-MBOAT4 system is a signaling pathway that alerts the central nervous system to the presence of dietary calories, rather than to their absence, as had been commonly accepted.
Role in Prader-Willi Syndrome
To determine whether ghrelin is elevated in Prader-Willi syndrome (PWS; 176270), Delparigi et al. (2002) measured fasting plasma ghrelin concentration, body composition, and subjective ratings of hunger in 7 subjects with PWS and 30 healthy subjects who had fasted overnight. The mean plasma ghrelin concentration was higher in PWS than in the reference population and this difference remained significant after adjustment for percentage of body fat. A positive correlation was found between plasma ghrelin and subjective ratings of hunger. The authors concluded that ghrelin is elevated in subjects with PWS. They also suggested that ghrelin may be responsible, at least in part, for the hyperphagia observed in PWS.
Haqq et al. (2003) measured fasting serum ghrelin levels in children with PWS with an average age of 9.5 years and body mass index (BMI) of 31.3 kilograms per square meter. The PWS group was compared with 4 control groups: normal weight controls, obese children, and children with melanocortin-4 receptor mutations and leptin deficiency. Ghrelin levels in children with PWS were significantly elevated (3-4 fold) compared with BMI-matched obese controls. The authors concluded that elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS.
Feigerlova et al. (2008) studied total plasma ghrelin levels in 40 children with PWS and 84 controls from 2 months to 17 years. Plasma ghrelin levels were higher in children with PWS than controls, both in the youngest children below 3 years who were not receiving GH (139250) (771 vs 233 pg/ml, P less than 0.0001) and in the children older than 3 years, all of whom were treated with GH (428 vs 159 pg/ml, P less than 0.0001). The authors concluded that plasma ghrelin levels in children with PWS are elevated at any age, including during the first years of life, thus preceding the development of obesity.
Obestatin
In addition to ghrelin, the preproghrelin peptide also produces obestatin. Contrary to the appetite-stimulating effects of ghrelin, Zhang et al. (2005) demonstrated that treatment of rats with obestatin suppressed food intake, inhibited jejunal contraction, and decreased body weight gain. Intraperitoneal injection of amidated human obestatin in adult male mice resulted in suppressed food intake in a time- and dose-dependent manner. Intracerebroventricular treatment with obestatin also decreased food intake, similar to the anorexigenic effect of the synthetic melanocortin (176830) agonist MTII (melanotan-II). In contrast, treatment with the nonamidated obestatin was less effective.
Chartrel et al. (2007) were unable to reproduce the finding of Zhang et al. (2005) that obestatin bound to the orphan G protein-coupled receptor GPR39 (602886). In response to the comments by Chartrel et al. (2007), Zhang et al. (2007) stated that they also could not reproduce this finding. However, Zhang et al. (2007) stated that they could reproduce their original findings on the in vivo effects of obestatin in mice (decrease in food intake, gastric emptying responses, and body weight gain) under precise experimental conditions.
Korbonits et al. (2002) studied the ghrelin gene in a group of 70 tall and obese children. They found 10 SNPs. One common polymorphism of the ghrelin gene, leu72 to met (L72M; 605353.0002), corresponding to an amino acid change in the tail of the preproghrelin molecule, was significantly associated with children with a higher BMI (P = 0.001), and with lower insulin secretion during the first part of an oral glucose tolerance test (P = 0.05), although no difference in glucose levels was noted. The authors concluded that variations in the ghrelin gene contribute to obesity in children and may modulate glucose-induced insulin secretion.
Ukkola et al. (2001) reported an arg51-to-gln polymorphism (R51Q; 605353.0001) in the ghrelin gene associated with obesity.
Hinney et al. (2002) screened the ghrelin 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). They found 2 previously described SNPs, R51Q (605353.0001) and L72M (605353.0002), in similar frequencies in study groups 1 and 2. Hence, they could not confirm the previous finding. Additionally, 2 novel variants were identified within the coding region. They detected a nonconservative amino acid change from gln to leu at codon 90 (605353.0003). They also detected a frameshift mutation (605353.0004) in 1 healthy normal-weight individual. The authors concluded that none of the variants seem to influence weight regulation.
To determine whether mutations in GHRL influence eating behavior and risk for metabolic syndrome (see 605552), obesity, diabetes, and related traits, Steinle et al. (2005) genotyped 856 Amish samples for 3 missense polymorphisms in GHRL, R51Q (605363.0001), L72M (605363.0002) (rs696217), and Q90L (605363.0003) (rs4684677) and performed association analyses with eating behavior traits and metabolic syndrome. The prevalence of metabolic syndrome was lower among those carrying the 51Q allele (3.8 vs 15.8%; age- and sex-adjusted odds ratio = 0.22; P = 0.031). The L72M variant was also associated with increased prevalence of metabolic syndrome (23.2 vs 13.4%; age- and sex-adjusted odds ratio = 2.57; P = 0.02) as well as higher fasting glucose, lower high density lipoprotein, and higher triglyceride levels (P = 0.02, P = 0.007, and P = 0.04, respectively). The 2 variants were not in linkage disequilibrium with each other, suggesting independent effects. The authors concluded that mutations in GHRL may confer risk for the metabolic syndrome.
Wortley et al. (2004) generated ghrelin-null mice which were viable and exhibited normal growth rates as well as normal spontaneous food intake patterns, normal basal levels of hypothalamic orexigenic and anorexigenic neuropeptides, and no impairment of reflexive hyperphagia after fasting. Wortley et al. (2004) concluded that endogenous ghrelin is not an essential regulator of food intake. Analyses of the ghrelin-null mice demonstrated increased use of fat as a fuel source when placed on a high-fat diet, indicating that endogenous ghrelin plays a prominent role in determining the type of metabolic substrate (e.g., fat vs carbohydrate) that is used for maintenance of energy balance, particularly under conditions of high fat intake.
Wortley et al. (2005) demonstrated that male Ghrl-null mice are protected from the rapid weight gain induced by early exposure to a high-fat diet; the reduced weight gain was associated with decreased adiposity and increased energy expenditure and locomotor activity as the animals aged. Despite the absence of ghrelin, these Ghrl-null mice showed a paradoxical preservation of the GH/IGF1 (147440) axis. Wortley et al. (2005) suggested that endogenous ghrelin plays an important role in the metabolic adaptation to nutrient availability.
Zigman et al. (2005) generated Ghsr (601898)-null mice and observed that ghrelin administration failed to acutely stimulate food intake or activate arcuate nucleus neurons. When fed a high-fat diet, both female and male Ghsr-null mice ate less food, stored less of their consumed calories, preferentially utilized fat as an energy substrate, and accumulated less body weight and adiposity than control mice. Ghsr-null mice also demonstrated statistically significant reductions in both respiratory quotient and locomotor activity compared to wildtype, and their blood glucose levels were significantly lower than wildtype mice of similar weight and body composition. Zigman et al. (2005) concluded that ghrelin-responsive pathways are an important component of coordinated body weight control, and suggested that ghrelin signaling is required for development of the full phenotype of diet-induced obesity.
In rats undergoing chronic intracerebroventricular infusion of ghrelin, Theander-Carrillo et al. (2006) observed increases in the glucose utilization rate of white and brown adipose tissue with no effect on skeletal muscle. In white adipocytes, mRNA expression of various fat storage-promoting enzymes was markedly increased, whereas mRNA expression of CPT1A (600528), which controls the rate-limiting step in fat oxidation, was decreased. In brown adipocytes, central ghrelin infusion resulted in lowered expression of the thermogenesis-related mitochondrial UCP1 (113730) and UCP3 (602044). These ghrelin effects were dose-dependent, occurred independently of ghrelin-induced hyperphagia, and seemed to be mediated by the sympathetic nervous system; none of the effects on adipocyte metabolism were observed following peripheral administration of equal amounts of ghrelin. Theander-Carrillo et al. (2006) concluded that central ghrelin is of physiologic relevance in the control of cell metabolism in adipose tissue.
Dixit et al. (2007) reported that ghrelin and ghrelin receptor expression within the thymus diminished with progressive aging. Infusion of ghrelin into 14-month-old mice significantly improved age-associated changes in thymic architecture and thymocyte numbers, increasing recent thymic emigrants and improving T cell receptor diversity of peripheral T cell subsets. Ghrelin-induced thymopoiesis during aging was associated with enhanced early thymocyte progenitors and bone marrow-derived hematopoietic stem cells, while Ghrl/Ghsr-deficient mice displayed accelerated age-associated thymic involution. Leptin (164160) also enhanced thymopoiesis in aged but not young mice.
Jerlhag et al. (2009) provided evidence that the central ghrelin signaling system is required for alcohol reward. In mice, central ghrelin administration to brain ventricles, or to tegmental areas involved in reward, increased voluntary alcohol intake. Central or peripheral administration of ghrelin receptor antagonists suppressed alcohol intake. In addition, suppression of central ghrelin signaling resulted in blunting of alcohol-induced locomotor stimulation, decreased dopamine release, and impaired conditioned place preference. These findings indicated that central ghrelin signaling not only stimulates the reward system, but is also required for stimulation of that system by alcohol.
In 6 of 96 obese (601665) subjects, Ukkola et al. (2001) found a substitution of gln for arg at codon 51 of preproghrelin (R51Q). This mutation was caused by a G-to-A transition at codon 346 of the ghrelin gene, leading to a replacement of arg by gln at the last codon of the mature ghrelin product, codon 28. This mutation was not found among 96 control subjects. Hinney et al. (2002) found this mutation in similar frequency among obese and control subjects, however.
In a study examining the relationship between GHRL variants and eating behavior and risk for metabolic syndrome (see 605552), obesity, diabetes, and related traits involving 856 Amish participants, Steinle et al. (2005) found that the prevalence of metabolic syndrome was lower among those carrying the 51Q allele (3.8 vs 15.8%; age- and sex-adjusted odds ratio = 0.22; P = 0.031).
Ukkola et al. (2001) found this mutation, a nucleotide 408C-A transversion resulting in a leu72-to-met (L72M) amino acid change, in 15 obese (601665) (12 heter- and 3 homozygotes) and 12 control subjects. Among the obese carriers, 12 were heterozygous and 3 homozygous for the substitution; among the control carriers, all were heterozygotes. This mutation is outside the coding region for mature ghrelin. The age at onset of self-reported weight problems tended to be lower among carrier obese subjects than among those without the polymorphism.
Korbonits et al. (2002) found this SNP (rs696217), which they referred to as SNP247, in heterozygosity in 14 subjects. They noted that children carrying this polymorphism had a significantly higher Z BMI compared to those carrying only the wildtype allele, and that the age at onset of obesity for those carrying this SNP was slightly earlier (median SNP247 group 2.0 years, wildtype group 3.5 years; P = 0.036).
Hinney et al. (2002) identified this variant in both extremely obese children and adolescents and normal-weight students.
In a study examining the relationship between GHRL variants and eating behavior and risk for metabolic syndrome (see 605552), obesity, diabetes, and related traits involving 856 Amish participants, Steinle et al. (2005) found that the L72M variant was associated with increased prevalence of metabolic syndrome (23.2 vs 13.4%; age- and sex-adjusted odds ratio = 2.57; P = 0.02) as well as higher fasting glucose, lower high density lipoprotein, and higher triglyceride levels (P = 0.02, P = 0.007, and P = 0.04, respectively).
Hinney et al. (2002) identified a novel variant in the ghrelin gene, an A-to-T transversion that led to a nonconservative amino acid change from gln to leu at codon 90 (Q90L; rs4684677). The frequency of the leu90 allele was significantly higher in the extremely obese (601665) children and adolescents than in the normal-weight students. Additionally, they genotyped 134 underweight students and 44 normal-weight adults for this SNP. Genotype frequencies were similar in extremely obese children and adolescents, underweight students, and normal-weight adults.
In a healthy normal-weight individual, Hinney et al. (2002) identified a 2-bp deletion at codon 34 of ghrelin leading to the insertion of 36 aberrant amino acids and a stop codon at position 71. This variant affects the coding region of mature ghrelin; presumably, this individual is haploinsufficient for ghrelin.
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Checchi, S., Montanaro, A., Pasqui, L., Ciuoli, C., Cevenini, G., Sestini, F., Fioravanti, C., Pacini, F. Serum ghrelin as a marker of atrophic body gastritis in patients with parietal cell antibodies. J. Clin. Endocr. Metab. 92: 4346-4351, 2007. [PubMed: 17711921] [Full Text: https://doi.org/10.1210/jc.2007-0988]
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