Ghrelin, a novel growth-hormone-releasing and appetite-stimulating peptide from stomach

doi:10.1016/j.beem.2004.07.001

Best Practice & Research Clinical Endocrinology & Metabolism

Volume 18, Issue 4, December 2004, Pages 517-530

https://doi.org/10.1016/j.beem.2004.07.001 Get rights and content

Recent identification of novel appetite-regulating hormones has revealed the complex interactions of these humoral factors in the regulation of feeding behavior in mammals. One of these hormones, ghrelin, a natural ligand of the orphan receptor GHS-R, purified from stomach, is able to stimulate growth hormone release from pituitary cells. Ghrelin is a 28 amino acid peptide containing an n-octanoylated serine 3 residue that is essential for its activity. Ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, the region known to control food intake. As an orexigenic peptide, ghrelin is therefore an endogenous regulator of feeding behavior from the peripheral tissues to the central nervous system.

Section snippets

Purification of ghrelin

Ghrelin was named from ghre, a word root in Proto-Indo-European languages for ‘grow’.⁴ Its name also implies that this peptide stimulates GH release.

The purification steps of ghrelin are outlined in Figure 1. By screening several tissues, a high amount of ghrelin was unexpectedly found in stomach extracts. Purified ghrelin is a 28 amino acid peptide with an essential n-octanoyl modification at serine 3 (Figure 2), the first-known example of a bioactive peptide modified by an acyl acid. In fact,

Sequence comparison of mammalian ghrelin

We also determined the amino acid sequences of mouse, bovine, porcine, ovine and canine ghrelins (Figure 3) and found them to be well conserved. In particular, the N-terminal ten amino acids are universally identical. The structural conservation and strictly required acyl modification indicate that the N-terminal portion of the peptide is of central importance in its activity peptide. Bovine and ovine ghrelins comprise 27 amino acids, like des-Gln¹⁴-ghrelin, the second endogenous form of rat

Tissue distribution of ghrelin

Ghrelin is mainly produced in the stomach. In situ hybridization and immunohistochemical analysis has indicated that ghrelin is produced in a distinct endocrine cell type found in the mucosal layer of the stomach.⁸ These cells, known as X/A-like cells, contain round, compact, electron-dense granules and are filled with ghrelin.9., 10. Fetal stomach exhibits no ghrelin expression, whereas after birth ghrelin expression increases in the stomach.¹¹ Ghrelin-immunoreactive cells are also found in

Measurement of ghrelin

The active form of ghrelin is an acyl-modified ghrelin, and the modification of ghrelin is easily cleaved during the extraction of samples. Moreover, peptide samples are easily digested by many cellular proteases. To measure ghrelin concentrations correctly in the plasma and tissues, we therefore have to inhibit the cleavage of the acyl modification of ghrelin and the protease digestion of the ghrelin peptide portion.

To measure plasma ghrelin concentrations, it is necessary to use EDTA and

Regulation of ghrelin secretion

Ghrelin secretion is controlled by feeding. Plasma ghrelin concentration is increased during fasting conditions and decreased after food intake.23., 24. It is not clear what factors are involved in the regulation of ghrelin secretion, but blood glucose levels may be critical.6., 25. Indeed, the oral or intravenous administration of glucose decreases plasma ghrelin concentration.⁶ On the other hand, gastric distention by water intake alone does not affect ghrelin levels. Plasma ghrelin

Ghrelin is a GH-releasing peptide

Although GH release from the pituitary is known to be stimulated by hypothalamic GH-releasing hormone (GHRH), ghrelin induces GH release via a different pathway from that of GHRH.³⁴ GHRH acts on the GHRH receptor to increase intracellular cAMP, which serves as a second messenger. On the other hand, ghrelin acts on the ghrelin receptor (GHS-R), increasing intracellular calcium concentration via inositol 1,4,5-trisphosphate signal transduction.4., 34.

Ghrelin stimulates GH release both in vitro

Ghrelin is an orexigenic peptide

Immunohistochemical analyses indicate that ghrelin-containing neural cells are found in the arcuate nucleus of the hypothalamus, a region involved in the regulation of appetite.4., 14. In addition, recent report indicates that ghrelin has also been detected in previously uncharacterized hypothalamic neurons lying adjacent to the third ventricle between the dorsal, ventral, paraventricular and arcuate hypothalamic nuclei.⁴² These ghrelin-containing neurons send efferents fibers to the neurons

Ghrelin and gastric bypass surgery

Gastric bypass surgery is often performed to treat severe obesity.⁵⁹ The purpose of the gastric bypass operation is to reduce the amount of space available for food in the gastric cavity and hence reduce the total calorie intake. The exact mechanism of action underlying this operation is, however, unknown.

Recent research has revealed that ghrelin might contribute to the body weight-reducing effects of gastric bypass surgery.29., 60., 61., 62., 63., 64. After gastric bypass resulting in an

Cardiovascular function

The fact that mRNA expression of the ghrelin receptor is observed in the heart and aorta, and that the intravenous injection of ghrelin into human volunteers induces a fall in blood pressure, indicates that ghrelin has some cardiovascular action.65., 66., 67.

An intravenous bolus of human ghrelin (10 μg/kg) significantly decreased mean arterial pressure (−12 mmHg) without a significant change in heart rate.65., 68. Ghrelin increased the cardiac index and stroke volume indices. Rats with chronic

Ghrelin genome variant and obesity

A relationship between ghrelin genome variant and obesity has been suggested.70., 71., 72., 73. In humans, two polymorphisms have been reported: Arg51Gln and Leu72Met (Figure 7). The former polymorphism changes the C-terminal processing site of ghrelin, resulting in a lack of the normal cleavage that is necessary to produce 28 amino acid ghrelin, but it may produce a pro-ghrelin peptide of 94 amino acids. For both variations, allelic frequencies were similar in obese patients and controls.

Anorexia nervosa

Anorexia nervosa is a syndrome often seen in young women that combines weight loss, amenorrhea and behavioral changes. Some of these changes are reversible with weight gain. Plasma ghrelin levels in AN patients are high and returned to control levels after renutrition.31., 32. Moreover, plasma GH levels are markedly elevated in AN patients. The high ghrelin and GH levels in AN patients return to basal levels after weight gain resulting from treatment. More research is needed to determine

Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a complex genetic disorder characterized by mild mental retardation, hyperphagia, short stature, muscular hypotonia and distinctive behavioral features.⁷⁴ The excessive appetite seen in PWS causes progressive severe obesity, which in turn leads to increased cardiovascular morbidity and mortality. The PWS genotype is characterized by a loss of one or more paternal genes in the region q11–q13 on chromosome 15. It is assumed that the genetic alteration leads to a

Summary

The discovery of the endogenous ligand for GHS-R, ghrelin, opened up a new field in hormone research. Ghrelin is a peptide hormone in which the third amino acid, usually serine but in some species threonine, is modified by an acyl acid; this modification is essential for ghrelin's activity. Ghrelin exists not only in mammalian species, but also in non-mammalian species such as frog, chicken and fish. Ghrelin may thus be an essential hormone for maintaining GH release and energy homeostasis in

Acknowledgements

We would like to thank Hisayuki Matsuo, Yukari Date, Masamitsu Nakazato and Noboru Murakami for their help and collaboration. This work was supported by the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN), a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to M.K.) and a Grant-in-Aid for the Promotion of Fundamental Studies in Health Science from the Organization for Pharmaceutical

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Ghrelin ameliorates transformation of hepatic ischemia-reperfusion injury to liver fibrosis by blocking Smad and ERK signalling pathways, and promoting anti-inflammation and anti-oxidation effects
2022, Transplant Immunology
Ghrelin, a gut hormone with pleiotropic effects, may act as a protective signal in parenchymal cells. Hepatic ischemia-reperfusion injury (HIRI) causes acute-on-chronic liver failure and induces transformation of acute to chronic injury. HIRI model of mice was established by a semi-hepatic blocking method and treated with Ghrelin. This process is involved in inflammation, oxidative stress damage and apoptosis, and is associated with the expansion and activation of fibrotic haematopoietic stem cells (HSCs) which express and secrete high levels of collagen that induces liver fibrosis. Therefore, we investigated the effects of Ghrelin during transformation of HIRI to liver fibrosis, and explored the molecular mechanism of Ghrelin's action based on Smad and ERK pathways.
Hepatic injury was detected by plasma ALT levels. The hepatic histology and collagen were elucidated by HE staining and Masson staining, respectively. Liver inflammation levels and inflammatory cell counts were assessed by MPO and HE staining, respectively. The antioxidant capacity of plasma was evaluated based on the levels of SOD, MDA, and XOD. The mRNA or protein expression levels of genes related to apoptosis, fibrosis, Smad, and ERK pathways were assessed by real-time quantitative PCR (RT-qPCR), ELISA, or western blotting.
The HIRI model was established to investigate the effects of the liver injury transformed to liver fibrosis. Ghrelin exhibited good hepatic protection by ameliorating liver histological changes and decreasing plasma ALT levels. Ghrelin significantly decreased the expression of MPO than that in model group, suggesting that Ghrelin blocked the inflammatory response in the HIRI liver tissue; this supports the anti-inflammatory effects of Ghrelin. Ghrelin significantly decreased apoptosis (enhanced Bcl-2 expression, and down-regulated Bax and Caspase 3). Ghrelin exhibited anti-oxidative effects as it inhibited plasma MDA levels, and promoted plasma SOD and XOD levels. Moreover, Ghrelin inhibited activation of hepatic stellate cells, blocked traditional fibrotic Smad and ERK signalling pathways, and reduced hepatic fibrosis by stimulating degradation of extracellular matrices (ECMs; such as collagen I, collagen III, HA, and LN).
This study demonstrates that Ghrelin delays the transformation of HIRI to liver fibrosis process which is correlated to its anti-apoptotic, anti-inflammatory, and anti-oxidative effects. Moreover, Ghrelin alleviates HIRI-mediated liver fibrosis, inhibits activation of HSCs, and reduces accumulation of ECM via inhibition of Smad and ERK signalling pathways.
Assessing the role of ghrelin and the enzyme ghrelin O-acyltransferase (GOAT) system in food reward, food motivation, and binge eating behavior
2021, Pharmacological Research
Citation Excerpt :
Ghrelin is the first known example of a bioactive peptide modified by an acylation reaction performed by the enzyme ghrelin O-acyltransferase (GOAT) [3,4]. Two principal forms of ghrelin peptide are observed in tissues and in plasma: the active n-octanoyl-modified form and the non-modified form, known as des-acyl-ghrelin (DAG), which lacks the ability to activate GHSR1a [1,5,6]. The main site of ghrelin production is the stomach; in situ hybridization and immunohistochemistry analysis revealed that ghrelin is synthesized by distinct endocrine cells of the gastric oxyntic glands, specifically the X/A-like cells, which contain round, compact, and electron-dense granules filled with ghrelin [7–10].
The peripheral peptide hormone ghrelin is a powerful stimulator of food intake, which leads to body weight gain and adiposity in both rodents and humans. The hormone, thus, increases the vulnerability to obesity and binge eating behavior. Several studies have revealed that ghrelin’s functions are due to its interaction with the growth hormone secretagogue receptor type 1a (GHSR1a) in the hypothalamic area; besides, ghrelin also promotes the reinforcing properties of hedonic food, acting at extra-hypothalamic sites and interacting with dopaminergic, cannabinoid, opioid, and orexin signaling. The hormone is primarily present in two forms in the plasma and the enzyme ghrelin O-acyltransferase (GOAT) allows the acylation reaction which causes the transformation of des-acyl-ghrelin (DAG) to the active form acyl-ghrelin (AG). DAG has been demonstrated to show antagonist properties; it is metabolically active, and counteracts the effects of AG on glucose metabolism and lipolysis, and reduces food consumption, body weight, and hedonic feeding response. Both peptides seem to influence the hypothalamic–pituitary–adrenal (HPA) axis and the corticosterone/cortisol level that drive the urge to eat under stressful conditions. These findings suggest that DAG and inhibition of GOAT may be targets for obesity and bingeing-related eating disorders and that AG/DAG ratio may be an important potential biomarker to assess the risk of developing maladaptive eating behaviors.
Ghrelin and cannabinoids require the ghrelin receptor to affect cellular energy metabolism
2013, Molecular and Cellular Endocrinology
Citation Excerpt :
There are two splicing variants of the GHS-R gene: the functioning full-length product GHS-R1a and a truncated variant GHS-R1b. One of the most important established roles of ghrelin is the regulation of appetite and energy homeostasis (Kojima et al., 2004; Korbonits et al., 2004). Both central and peripheral administrations of ghrelin cause an increase in appetite and body weight (Kamegai et al., 2001; Tschop et al., 2000; Wren et al., 2001a).
Ghrelin is a potent orexigenic brain-gut peptide with lipogenic and diabetogenic effects, possibly mediated by growth hormone secretagogue receptor (GHS-R1a). Cannabinoids also have orexigenic and lipogenic effects. AMPK is a regulator of energy homeostasis and we have previously shown that ghrelin and cannabinoids stimulate hypothalamic AMPK activity while inhibiting it in the liver and adipose tissue, suggesting that AMPK mediates both the central appetite-inducing and peripheral effects of ghrelin and cannabinoids.
Using GHS-R KO mice, we investigated whether the known ghrelin receptor GHS-R1a is required for the tissue-specific effects of ghrelin on AMPK activity, and if an intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity.
Wild-type and GHS-R KO mice were treated intraperitoneally with ghrelin 500 ng/g bodyweight or CB1 agonist HU210 20 ng/g and hypothalamic, hepatic and adipose AMPK activity was studied using a functional kinase assay.
Ghrelin and HU210 significantly stimulated hypothalamic AMPK activity in wild-type animals (mean ± SEM, 122.5 ± 5.2% and 128 ± 11.6% of control, p < 0.05) and inhibited it in liver (55.1 ± 4.8% and 62.2 ± 14.5%, p < 0.01) and visceral fat (mesenteric fat (MF): 54.6 ± 16% and 52.0 ± 9.3%, p < 0.05; epididymal fat (EF): 47.9 ± 12.1% and 45.6 ± 1.7%, p < 0.05). The effects of ghrelin, and interestingly also HU210, on hypothalamic, visceral fat and liver AMPK activity were abolished in the GHS-R KO mice (hypothalamus: 107.9 ± 7.7% and 87.4 ± 13.3%, liver: 100.5 ± 11.6% and 116.7 ± 5.4%, MF: 132.1 ± 29.9% and 107.1 ± 32.7%, EF: 89.8 ± 7.3% and 91.7 ± 18.3%, p > 0.05).
Ghrelin requires GHS-R1a for its effect on hypothalamic, liver and adipose tissue AMPK activity. An intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity.
Ghrelin At the Interface of Obesity and Reward
2013, Vitamins and Hormones
Citation Excerpt :
With obesity being one of the leading causes of illness and mortality the development of novel strategies to reduce body weight as well as alleviate associated diseases within the metabolic syndrome are urgently sought after. Ghrelin is the only peripheral derived orexigenic hormone, which acts centrally to regulate food intake and body weight homeostasis (Kojima, Hosoda, & Kangawa, 2004; Nakazato et al., 2001; Tschop et al., 2000). Therefore, it is not surprising that the obesity epidemic has led to the attention and effort of the pharmaceutical industry to the development of antiobesity drugs targeting the ghrelinergic system (Chollet, Meyer, & Beck-Sickinger, 2009; Leite-Moreira & Soares, 2007; Lu et al., 2009; Moulin, Ryan, Martinez, & Fehrentz, 2007; Soares et al., 2008; Zorrilla et al., 2006).
The prevalence of obesity continues to increase and has reached epidemic proportions. Accumulating data over the past few decades have given us key insights and broadened our understanding of the peripheral and central regulation of energy homeostasis. Despite this, the currently available pharmacological treatments, reducing body weight, remain limited due to poor efficacy and side effects. The gastric peptide ghrelin has been identified as the only orexigenic hormone from the periphery to act in the hypothalamus to stimulate food intake. Recently, a role for ghrelin and its receptor at the interface between homeostatic control of appetite and reward circuitries modulating the hedonic aspects of food has also emerged. Nonhomeostatic factors such as the rewarding and motivational value of food, which increase with food palatability and caloric content, can override homeostatic control of food intake. This nonhomeostatic decision to eat leads to overconsumption beyond nutritional needs and is being recognized as a key component in the underlying causes for the increase in obesity incidence worldwide. In addition, the hedonic feeding behavior has been linked to food addiction and an important role for ghrelin in the development of addiction has been suggested. Moreover, plasma ghrelin levels are responsive to conditions of stress, and recent evidence has implicated ghrelin in stress-induced food-reward behavior. The prominent role of the ghrelinergic system in the regulation of feeding gives rise to it as an effective target for the development of successful antiobesity pharmacotherapies that not only affect satiety but also selectively modulate the rewarding properties of food and reduce the desire to eat.
Effect of polymorphisms at the ghrelin gene locus on carcass, microstructure and physicochemical properties of longissimus lumborum muscle of Polish Landrace pigs
2011, Meat Science
The influence of RFLP–BsrI polymorphisms at the ghrelin gene locus on carcass, meat quality parameters and muscle fiber characteristics of longissimus lumborum was studied in 168 barrows of the Polish Landrace breed. Analysis revealed a high frequency of the 1 allele (0.60) with the frequencies of the 11, 12 and 22 genotypes being 0.45, 0.30 and 0.25, respectively. The most favorable parameters of meat traits were characteristic of pigs with the 22 genotype, together with a higher carcass and loin weight and lower thermal loss compared to 12 heterozygotes. The highest fat content was found in pigs with the 11 genotype, which had the highest abdominal fat weight and mean backfat thickness. Meanwhile, the 12 heterozygotes were characterized by the largest loin eye areas, highest lightness (L*) and yellowness (b*) values, and lowest redness (a*) values, as well as the greatest hardness and chewiness and largest diameter of type IIB muscle fibers compared to the other genotypes.
Distribution of pepsinogen- and ghrelin-producing cells in the digestive tract of Japanese eel (Anguilla japonica) during metamorphosis and the adult stage
2011, General and Comparative Endocrinology
Pepsinogen is the precursor form of the gastric-specific digestive enzyme, pepsin. Ghrelin is a representative gastric hormone with multiple functions in vertebrates, including the regulation of growth hormone release, stimulation of food intake and gastrointestinal motility function. We investigated chronological changes in the distribution of pepsinogen-expressing cells by in situ hybridization and ghrelin-immunoreactive cells by immunohistochemistry in the Japanese eel (Anguilla japonica) during metamorphosis from the leptocephalus sage to the elver stage. The ghrelin-producing cells first appeared in the gastric cecum and pyloric portion of the stomach in the late phase of metamorphosing leptocephali, whereas the pepsinogen-producing cells were first detected in the early phase of the glass-eel stage. These suggest that endocrine cells differentiated earlier than exocrine cells in the eel stomach. Accompanying eel development, the distribution of ghrelin-producing cells spread to the esophagus and other regions of the stomach, but not to the intestine. These results may be related to the changes in dietary habits during metamorphosis in the Japanese eel.

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5Ghrelin, a novel growth-hormone-releasing and appetite-stimulating peptide from stomach

Section snippets

Purification of ghrelin

Sequence comparison of mammalian ghrelin

Tissue distribution of ghrelin

Measurement of ghrelin

Regulation of ghrelin secretion

Ghrelin is a GH-releasing peptide

Ghrelin is an orexigenic peptide

Ghrelin and gastric bypass surgery

Cardiovascular function

Ghrelin genome variant and obesity

Anorexia nervosa

Prader-Willi syndrome

Summary

Acknowledgements

Trends Neuroscience

Journal Biological Chemistry

International Review of Cytology

Biochemistry Biophysics Research Communications

Journal of Biological Chemistry

Neuroscience Letters

Brain Research Molecular Brain Research

Regulatory Peptides

Biochemical and Biophysical Research Communications

Neuron

Neuroscience Letters

Gastroenterology

Central nervous system control of food intake

Nature

Leptin and the regulation of body weight in mammals

Nature

Ghrelin is a growth-hormone-releasing acylated peptide from stomach

Nature

A role for ghrelin in the central regulation of feeding

Nature

Ghrelin induces adiposity in rodents

Nature

Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans

Endocrinology

Morphology and function of the entero-endocrine cells

Hormone and Metabolic Research

Ghrelin in neonatal rats: distribution in stomach and its possible role

Journal of Endocrinology

Hypothalamic growth hormone secretagogue-receptor (GHS-R) expression is regulated by growth hormone in the rat

Endocrinology

Growth hormone secretagogue binding sites in peripheral human tissues

The Journal of Clinical Endocrinology and Metabolism

Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines

The Journal of Clinical Endocrinology and Metabolism

Hemodynamic and hormonal effects of human ghrelin in healthy volunteers

American Journal of Physiology. Regulatory, Integrative and Comparative Physiology

Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion

Diabetes

Ghrelin cells replace insulin-producing {beta} cells in two mouse models of pancreas development

Proceedings of the National Academy of Science, USA

A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans

Diabetes

Post-prandial decrease of circulating human ghrelin levels

Journal of Endocrinological Investigation

Insulin regulates plasma ghrelin concentration

The Journal of Clinical Endocrinology and Metabolism

Effects of glucose, free fatty acids or arginine load on the GH-releasing activity of ghrelin in humans

Clinical Endocrinology (Oxf)

Circulating ghrelin levels are decreased in human obesity

Diabetes

Weight loss increases circulating levels of ghrelin in human obesity

Clinical Endocrinology (Oxf)

Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery

New England Journal of Medicine

Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion

The Journal of Clinical Endocrinology and Metabolism

Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa

European Journal of Endocrinology

A role for the novel weight-regulating hormone ghrelin in anorexia nervosa

American Clinical Laboratory

Increased fasting plasma ghrelin levels in patients with bulimia nervosa

European Journal of Endocrinology

Intracellular signaling mechanisms mediating ghrelin-stimulated growth hormone release in somatotropes

Endocrinology

5
Ghrelin, a novel growth-hormone-releasing and appetite-stimulating peptide from stomach