Ghrelin

History and name

Ghrelin was discovered after the ghrelin receptor (called growth hormone secretagogue type 1A receptor or GHSR) was discovered in 1996 and was reported in 1999. The hormone name is based on its role as a growth hormone-releasing peptide, with reference to the Proto-Indo-European root ghre-, meaning "to grow".

Gene, transcription products, and structure

The GHRL gene produces mRNA which has four exons. Five products arise: the first is the 117-amino acid preproghrelin. (It is homologous to promotilin; both are members of the motilin family). It is cleaved to produce proghrelin which is cleaved to produce a 28-amino acid ghrelin (unacylated) and C-ghrelin(acylated). Obestatin is presumed to be cleaved from C-ghrelin.

Ghrelin only becomes active when caprylic (octanoic) acid is linked posttranslationally to serine at the 3-position by the enzyme ghrelin O-acyltransferase (GOAT). It is located on the cell membrane of ghrelin cells in the stomach and pancreas. The non-octanoylated form is desacyl ghrelin. It does not activate the GHSR receptor but does have other effects: cardiac, anti-ghrelin, appetite stimulation, and inhibition of hepatic glucose output Side-chains other than octanoyl have also been observed: these can also trigger the ghrelin receptor. In particular, decanoyl ghrelin has been found to constitute a significant portion of circulating ghrelin in mice, but as of 2011 its presence in humans has not been established.

Alternative names

The ghrelin cell is also known as an A-like cell (pancreas), X-cell (for unknown function), X/A-like cell (rats), Epsilon cell (pancreas), P/D sub 1 cell (humans) and Gr cell (abbreviation for ghrelin cell).

Location

Ghrelin cells are found mainly in the stomach and duodenum, but also in the jejunum, lungs, pancreatic islets, gonads, adrenal cortex, placenta, and kidney. It has recently been shown that ghrelin is produced locally in the brain

Features

Ghrelin cells are found in oxyntic glands (20% of cells), pyloric glands, and small intestine. They are ovoid cells with granules. They have gastrin receptors. Some produce nesfatin-1. Ghrelin cells are not terminally differentiated in the pancreas: they are progenitor cells that can give rise to A-cells, PP cells and Beta-cells there.

Function and mechanism of action

Ghrelin is a participant in regulating the complex process of energy homeostasis which adjusts both energy input – by adjusting hunger signals – and energy output – by adjusting the proportion of energy going to ATP production, fat storage, glycogen storage, and short-term heat loss. The net result of these processes is reflected in body weight, and is under continuous monitoring and adjustment based on metabolic signals and needs. At any given moment in time, it may be in equilibrium or disequilibrium. Gastric-brain communication is an essential part of energy homeostasis, and several communication pathways are probable, including the gastric intracellular mTOR/S6K1 pathway mediating the interaction among ghrelin, nesfatin and endocannabinoid gastric systems, and both afferent and efferent vagal signals.

Ghrelin and synthetic ghrelin mimetics (growth hormone secretagogues) increase body weight and fat mass by triggering receptors in the arcuate nucleus that include the orexigenic neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons. Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive. Ghrelin reduces the mechanosensitivity of gastric vagal afferents, so they are less sensitive to gastric distension.

In addition to its function in energy homeostasis, ghrelin also activates the cholinergic–dopaminergic reward link in inputs to the ventral tegmental area and in the mesolimbic pathway, a circuit that communicates the hedonic and reinforcing aspects of natural rewards, such as food and addictive drugs such as ethanol. Ghrelin receptors are located on neurons in this circuit. Hypothalamic ghrelin signalling is required for reward from alcohol and palatable/rewarding foods.

Ghrelin also improves endothelial function and inhibits proatherogenic changes in cell cultures. It activates the endothelial isoform of nitric oxide synthase in a pathway that depends on various kinases including Akt.

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. 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. This suggests that ghrelin acts as a body weight regulator, continuously keeping one's body weight and energy stores in check.

Blood levels

Blood levels are in the pmol/l range. Both active and total ghrelin can be measured. Circulating ghrelin concentrations rise before eating and fall afterward, more strongly in response to protein and carbohydrate than to lipids.

Ghrelin receptor

The ghrelin receptor GHSR1a (a splice-variant of the growth hormone secretagogue receptor, with the GHSR1b splice being inactive) is involved in mediating a wide variety of biological effects of ghrelin, including: stimulation of growth hormone release, increase in hunger, modulation of glucose and lipid metabolism, regulation of gastrointestinal motility and secretion, protection of neuronal and cardiovascular cells, and regulation of immune function. They are present in high density in the hypothalamus and pituitary, on the vagus nerve (on both afferent cell bodies and afferent nerve endings) and throughout the gastrointestinal tract.

Gastrointestinal tract

Ghrelin promotes intestinal cell proliferation and inhibits apoptosis during inflammatory states and oxidative stress. It also suppresses 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. 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 mucosal injury to the stomach.

Ghrelin promotes gastrointestinal and pancreatic malignancy.

Pancreas

Ghrelin inhibits glucose-stimulated insulin secretion from beta cells in the pancreatic islets. Ghrelin does this indirectly by promoting local negative feedback mediated by somatostatin from pancreatic delta cells, which selectively express the ghrelin receptor.

Glucose metabolism

The entire ghrelin system (dAG, AG, GHSR and GOAT) has a gluco-regulatory action.

Learning and memory

The hippocampus plays a significant role in neurotrophy: the cognitive adaptation to changing environments and the process of learning and it is a potent stimulator of growth hormone. 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 on human memory performance 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 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 levels trend lower and obesity is less likely.

Stress-induced fear

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.

Substantia nigra function

Ghrelin, through its receptor increases the concentration of dopamine in the substantia nigra.

Reproductive system

Ghrelin has inhibitory effects on gonadotropin-releasing hormone (GnRH) secretion. It may cause decreased fertility.

Fetus and neonate

Immune system

Ghrelin gene products have several actions on acute and chronic inflammation and autoimmunity, with promising therapeutic applications.

Anorexia and obesity

Gastric bypass surgery

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 nearly 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.

Medical management of obesity

Ghrelin is not FDA approved for any indication.

In rodents and pigs, an anti-obesity vaccine has been developed: it blocks the ghrelin receptor.

Aging

Ghrelin plasma concentration increases with age and this may contribute to the tendency for weight gain as people age.

Future clinical uses