Ghrelin

Ghrelin is a 28-amino acid hunger-stimulating peptide and hormone that is produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas. Ghrelin together with obestatin is produced from cleavage of the ghrelin/obestatin prepropeptide (also known as the appetite-regulating hormone or growth hormone secretagogue or motilin-related peptide), which in turn is encoded by the GHRL gene. The full-length preproghrelin is homologous to the promotilin protein classified in the motilin family, and is cleaved into the following two chains: (1) Ghrelin and (2) Obestatin. Ghrelin receptors are expressed in a wide variety of tissues, including the pituitary, stomach, intestine, pancreas, thymus, gonads, thyroid, and heart. The diversity of ghrelin receptor locations suggests ghrelin has diverse biological functions.

Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone leptin, produced by adipose tissue, which induces satiation when present at higher levels. In some bariatric procedures, the level of ghrelin is reduced in patients, thus causing satiation before it would normally occur.

Ghrelin is a potent stimulator of growth hormone secretion from the anterior pituitary gland. The ghrelin receptor is a G protein-coupled receptor, known as the growth hormone secretagogue receptor. Ghrelin binds to the GHSR1a splice-variant of this receptor, which is present in high density in the hypothalamus and pituitary as well as vagal afferent cell bodies and vagal afferent endings throughout the gastro-intestinal tract.

Ghrelin plays a significant role in neurotrophy, in particular in the hippocampus, and is essential for cognitive adaptation to changing environments and the process of learning. Ghrelin has been shown to activate the endothelial isoform of nitric oxide synthase in a pathway that depends on various kinases including Akt.

History and name
The discovery of ghrelin followed after the discovery of the growth hormone secretagogue type 1A receptor in 1996 and was reported by Masayasu Kojima and colleagues in 1999. The name is based on its role as a growth hormone-releasing peptide, with reference to the Proto-Indo-European root ghre, meaning to grow. (Growth Hormone Release-Inducing = Ghrelin)

Synthesis and variants
The mRNA from the GHRL gene codes for a 117-amino acid peptide called preproghrelin, containing 4 exons. The signalling peptide molecule of this larger precursor is cleaved to produce proghrelin. Proghrelin is cleaved in two to produce the 28-amino acid peptide ghrelin (unacylated) and C-ghrelin (of which obestatin is presumed to be a cleaved form).

'Ghrelin' usually refers to the octanoylated form of ghrelin (acyl ghrelin). This is the 28-amino acid peptide sequence with an octanoylation on the third amino acid (serine). The octanoylation is performed by the ghrelin O-acyltransferase (GOAT) protein (a member of the membrane-bound O-acyltransferase family of proteins), located in the stomach and pancreas. This peptide can activate the GHSR receptor and is, thus, known as the active form of ghrelin. The non-octanoylated form is known as desacyl ghrelin or the inactive form, and does not activate GHSR1a and, thus, does not release growth hormone like acyl ghrelin; however, studies have shown it has its own effects. Side-chains other than octanoyl have also been observed.

Mechanism of action
Ghrelin has emerged as the first identified circulating hunger hormone. Ghrelin is also the only known circulating orexigen, or appetite-enhancing hormone. It is produced mainly in the small and large intestines, but can also be secreted by the lungs, pancreatic islets, gonads, adrenal cortex, placenta, kidney, and brain. The diversity in areas of ghrelin production indicates that this hormone has widespread and numerous biological functions. Ghrelin and synthetic ghrelin mimetics (the growth hormone secretagogues) increase food intake and increase fat mass by an action exerted at the level of the hypothalamus. They activate cells in the arcuate nucleus that include the orexigenic neuropeptide Y (NPY) neurons. Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive. Ghrelin also activates the mesolimbic cholinergic-dopaminergic reward link, a circuit that communicates the hedonic and reinforcing aspects of natural rewards, such as food, as well as of addictive drugs, such as ethanol. Indeed, central ghrelin signalling is required for reward from alcohol. and palatable/rewarding foods. There is also strong evidence that ghrelin has a peripheral appetite modulatory effect on satiety by affecting the mechanosensitivity of gastric vagal afferents, making them less sensitive to distension resulting in overeating.

Relation to obestatin
Obestatin is a putative hormone that was described, in late 2005, to decrease appetite. Both obestatin and ghrelin are encoded by the same gene; the gene's product breaks apart to yield the two peptide hormones. The physiological value of this mechanism is unknown, and it should be noted that no secretory convertase is capable of cleaving the recombinant precursor by cleavage at the single basic residue required for generation of obestatin; thus, the physiological generation of this peptide is questionable.

Appetite Inducer
Ghrelin has been linked to inducing appetite and feeding behaviors. Circulating ghrelin levels are the highest right before a meal and the lowest right after. Injections of ghrelin in both humans and rats have been shown to increase food intake in a dose-dependent manner. So the more ghrelin that is injected the more food that is consumed. However, ghrelin does not increase meal size, only meal number. Ghrelin injections also increase an animal's motivation to seek out food, behaviors including increased sniffing, foraging for food, and hoarding food. Ghrelin also readies the body for the incoming nutrients by stimulating gastrointestinal motility and gastric acid secretions.

Anti-obesity vaccine
An anti-obesity vaccine that is directed against the hormone ghrelin in rodents and pigs has been developed. The vaccine uses the immune system, to be specific antibodies, to bind to selected targets, directing the body's own immune response against them. This prevents ghrelin from reaching the central nervous system, thus producing a desired reduction in weight gain.

Body weight regulation
Body weight is regulated through energy balance, the amount of energy taken in versus the amount of energy expended over an extended period of time. Studies have shown that ghrelin levels are negatively correlated with weight. This data suggests that ghrelin functions as an adiposity signal, a messenger between the body’s energy stores and the brain. When a person loses weight their ghrelin levels increase, which causes increased food consumption and weight gain. On the other hand, when a person gains weight, ghrelin levels drop, leading to a decrease in food consumption and weight loss (Tung, 2005). This suggests that ghrelin acts as a body weight regulator, continuously keeping one’s body weight and energy stores in check.

Gastrointestinal tract
Ghrelin has been proposed as a hormone that promotes intestinal cell proliferation and inhibits its apoptosis during inflammatory states and oxidative stress. It also suppresses the pro-inflammatory mechanisms and augments anti-inflammatory mechanisms, thus creating a possibility of its therapeutic use in various gastrointestinal inflammatory conditions, including colitis, ischemia reperfusion injury, and sepsis. In fact, animal models of colitis, ischemia reperfusion, and sepsis-related gut dysfunction have been shown to benefit from therapeutic doses of ghrelin. It has also been shown to have regenerative capacity and is beneficial in case of mucosal injury to the stomach. Ghrelin also enhances the motility of the gastrointestinal tract, as does motilin. Ghrelin also appears to promote gastrointestinal and pancreatic malignancy.

Learning and memory
Animal models indicate that ghrelin may enter the hippocampus from the bloodstream, altering nerve-cell connections, and so altering learning and memory. It is suggested that learning may be best during the day and when the stomach is empty, since ghrelin levels are higher at these times. A similar effect for human neural-physiology is possible. In rodents, X/A-like cells produce ghrelin.

Depression
Ghrelin knock out mice (who never express ghrelin) have increased anxiety in response to a variety of stressors, such as acute restraint stress and social stress in an experimental settings. In normal mice, ghrelin can stimulate the Hypothalamic-pituitary-adrenal axis, from the anterior pituitary.

Ghrelin has been shown to have implications for depression prevention. Antidepressant-like attributes were demonstrated when mice with high levels of ghrelin and mice with the ghrelin gene knocked out underwent social defeat stress and then were placed in the forced swim tank. Mice with elevated ghrelin swam more than ghrelin deficient mice. These ghrelin-deficient mice exhibited more social avoidance as well. These mice did not exhibit depression-like behaviors when injected with a commonly prescribed antidepressant, suggesting that ghrelin acts as a short-term natural adaptation against depression.

Sleep duration
Short sleep duration is associated with high levels of ghrelin and obesity. An inverse relationship between the hours of sleep and blood plasma concentrations of ghrelin exists; as the hours of sleep increase, ghrelin concentrations lower, thereby potentially reducing appetite and avoiding potential obesity.

Role in stress-induced anxiety disorders
Prior stress exposure heightens fear learning during Pavlovian fear conditioning. Stress-related increases in ghrelin circulation were shown to be necessary and sufficient for stress to increase fear learning. Ghrelin was found to be upregulated by stress even in the absence of adrenal hormones. Blocking the ghrelin receptor during stress abolished stress-related enhancement of fear memory without blunting other markers of stress. These results suggest that ghrelin is a novel branch of the stress response. Human studies are needed to translate the use of anti-ghrelin treatments to prevent stress-induced psychiatric disorders.

Other
Regarding the reproductive system, ghrelin has inhibitory effects on gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus, thus appearing to potentially cause decreased fertility.

In fetuses, it seems that ghrelin is produced early by the lung and promotes growth.

Clinical significance
Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals, suggesting that ghrelin does not contribute to obesity, except in the cases of Prader-Willi syndrome-induced obesity, where high ghrelin levels are correlated with increased food intake. Those suffering from the eating disorder anorexia nervosa have high plasma levels of ghrelin compared to both the constitutionally thin and normal-weight controls. One small single-blind study found that intravenous administration of ghrelin to anorexia nervosa patients increased food intake by 12–36% over the trial period.

The level of ghrelin increases during the time of day from midnight to dawn in thinner people, which suggests there is a flaw in the circadian system of obese individuals. Short sleep duration may also lead to obesity, through an increase of appetite via hormonal changes. Lack of sleep produces ghrelin, which stimulates appetite and creates less leptin, which, among its many other effects, suppresses appetite.

Ghrelin levels are also high in patients with cancer-induced cachexia.

At least one study found that gastric bypass surgery not only reduces the gut's capacity for food but also dramatically lowers ghrelin levels compared to both lean controls and those that lost weight through dieting alone. However, studies are conflicting as to whether or not ghrelin levels return to close to normal with gastric bypass patients in the long term after weight loss has stabilized. Bariatric surgeries involving vertical sleeve gastrectomy reduce plasma ghrelin levels by about 60% in the long term.

Ghrelin through its receptor increases the concentration of dopamine in the substantia nigra, a region of the brain where dopamine cell degeneration leads to Parkinson's disease. Hence, ghrelin may find application in slowing down the onset of Parkinson's disease.