Ghrelin

INTRODUCTION — Ghrelin is a 28-amino-acid peptide that is the natural ligand for the growth hormone secretagogue receptor (GHSR) [1,2]. Based on its structure, it is a member of the motilin family of peptides. When administered peripherally or into the central nervous system, ghrelin stimulates secretion of growth hormone, increases food intake, and produces weight gain [3,4].

Ghrelin, which is produced by the stomach, increases during periods of fasting or under conditions associated with negative energy balance such as starvation or anorexia. In contrast, ghrelin levels are low after eating or with hyperglycemia, and in obesity. Accumulating evidence indicates that ghrelin plays a central role in the neurohormonal regulation of food intake and energy homeostasis.

This topic review will provide an overview on the biology of ghrelin. Related subjects are discussed separately. (See "Obesity: Genetic contribution and pathophysiology" and "Obesity in adults: Drug therapy".)

TISSUE DISTRIBUTION — Ghrelin was discovered in 1999 when it was noted that tissue extracts from the rat stomach activated the growth hormone secretagogue receptor (GHSR) [1]. It has since been recognized that the stomach is the richest source of ghrelin (figure 1). Over 90 percent of the body's ghrelin is in the stomach and duodenum. Lower amounts are found in the pancreas, pituitary, kidney, and placenta. A limited region of the arcuate nucleus of the hypothalamus contains small amounts of ghrelin.

Ghrelin is most abundant in the gastric fundus where it is produced in oxyntic glands by distinctive endocrine cells known as P/D1 cells [5,6]. Ghrelin-containing cells are of two types:

●One type is open to the lumen of the stomach, where it is exposed to gastric contents.

●The second, closed type, is not open to the lumen of the gut but rather lies in close approximation to the capillary network of the lamina propria [7]. In this location, ghrelin is secreted into the vasculature.

STRUCTURE — The ghrelin gene is on chromosome 3p and is translated into a pre-propeptide that has a signal peptide typical of secretory proteins. Ghrelin shares structural similarity with motilin, although its 28-amino-acid structure is unique. A distinctive feature is a fatty acid chain modification on the serine residue at position 3, which is necessary for biological activity (figure 2). This rare posttranslational modification is achieved through the action of ghrelin O-acyl-transferase (GOAT) in ghrelin-producing cells. Ghrelin circulates in both acylated and unacylated forms known as ghrelin and desacyl-ghrelin, respectively [8]. Desacyl-ghrelin was originally thought to be a degradation product of ghrelin but is now believed to have distinct, albeit limited biological activity.

Obestatin is a 23-amino-acid peptide that is also encoded by the ghrelin gene. Obestatin, originally isolated from the rat stomach, was initially thought to oppose the effects of ghrelin on food intake. Treatment of rats with obestatin suppresses food intake, inhibits jejunal contraction, and decreases weight gain [9]. However, there is accumulating evidence that obestatin has multiple other effects. In the pancreas, obestatin is expressed along with ghrelin and may sustain beta cell survival [10]. Obestatin is also produced in adipose tissue, where it appears to have autocrine/paracrine effects to regulate growth and differentiation [11]. Elevated blood levels of obestatin have been reported in some cancers (eg, ovarian cancer), and it is possible that obestatin plays a paracrine role in cancer growth [12].

Ghrelin receptor — The ghrelin receptor (growth hormone secretagogue receptor [GHSR]) is a member of a G protein-coupled receptor (GPCR) subfamily that also includes receptors for motilin, neurotensin, and neuromedin U. Two forms of the receptor (GHSR1a and GHSR1b) exist and result from alternative mRNA splicing from a single gene.

GHSR1a is expressed in both the central nervous system and peripheral tissues. In the brain, GHSR1a expression is highest in the hypothalamus, but it is also found in the dorsal motor nucleus of the vagus and parasympathetic preganglionic neurons. In some hypothalamic nuclei, GHSR1a mRNA is co-expressed with neuropeptide Y (NPY) and agouti-related peptide (AgRP), which regulate food intake and satiety [13]. In peripheral tissues, GHSR1a is found in the anterior pituitary, islet cells of the pancreas, thyroid, adrenal glands, and heart. GHSR1a has also been located on autonomic afferent neurons and enteric nerves, but not on smooth muscle. GHSR1b is a truncated form of the receptor and although it is more widely distributed than GHSR1a, it does not interact with the G protein complex, and thus, its biological actions are unclear [14,15].

SECRETION — Ghrelin concentrations in the blood increase during fasting and surges occur shortly before meals. Ghrelin secretion appears to be a cephalic response, possibly under vagal and sympathetic nervous system control (figure 1) [16,17]. Preprandial ghrelin release can be entrained and may be important in preparing for meal ingestion [18].

Ghrelin levels decrease after eating. The suppressive effects of food on plasma ghrelin appear to be nutrient specific, with carbohydrates having the greatest effect, followed by protein and lipids. Postprandial suppression of ghrelin release is unrelated to meal effects on gastric distention or intraluminal nutrient exposure in either the stomach or duodenum but rather occurs through nonvagal neural signals from the intestine [19].

Ghrelin expression has been detected in some cancers, including the majority of gastric carcinoids and some intestinal and pancreatic neuroendocrine tumors [20]. In vitro studies have demonstrated a growth-promoting effect of ghrelin, and it has been speculated that ghrelin may potentiate cancer growth. In contrast, low baseline concentrations of ghrelin have been reportedly associated with gastric noncardia and esophagogastric junction cancers. This may be attributed to the finding that serum ghrelin levels decrease under conditions of chronic inflammation and atrophy. (See "Risk factors for gastric cancer", section on 'Precursor lesions'.)

In lean individuals, fasting plasma ghrelin levels are approximately 550 to 650 pg/mL. Circulating ghrelin levels are low in obesity (in the range of 200 to 350 pg/mL) and states of positive energy balance, and are inversely correlated with body mass index (BMI) [21-23]. Decreased plasma ghrelin levels have been associated with gastritis, with or without Helicobacter pylori infection, and it has been proposed that serum ghrelin levels may be a useful marker of gastric atrophy [24].

Ghrelin levels are high in fasting, cachexia, and anorexia, where fasting ghrelin levels average over 1000 pg/mL. Importantly, weight loss increases circulating ghrelin levels [25].

A number of reports indicate that the gut microbiome affects ghrelin secretion through the release of bacterial metabolites including lipopolysaccharides, hydrogen sulfide, short-chain fatty acids, and formyl peptides or other mechanisms [26]. However, these relationships are complex and incompletely understood.

GHRELIN ACTIONS — Intravenous administration of ghrelin potently stimulates growth hormone secretion and causes mild elevations of corticotropin (ACTH), cortisol, and prolactin (figure 1) [3]. Together, ghrelin and growth hormone-releasing hormone (GHRH) synergistically increase growth hormone levels [27]. It is likely that ghrelin's effects on growth hormone release are mediated through neural afferent vagal pathways and may involve stimulation of GHRH [28].

Food intake and energy balance — In addition to its effects on growth hormone secretion, ghrelin stimulates appetite and induces a positive energy balance that can lead to weight gain (figure 1) (see "Obesity: Genetic contribution and pathophysiology", section on 'Stimulators of food intake'). Ghrelin is implicated in regulating mealtime hunger and meal initiation [29]. Ghrelin is the first hormone to be identified that increases feeding when administered peripherally. All of the other known orexigenic peptide transmitters, such as neuropeptide Y (NPY), orexin, agouti-related peptide (AgRP), melanocortin-concentrating hormone (MCH), and galanin, stimulate feeding only when administered into the central nervous system. The observations that circulating ghrelin levels increase sharply before a meal and fall abruptly after a meal suggest that ghrelin serves as a signal for initiation of feeding. Interestingly, ghrelin increases the number but not the size of meals. However, ghrelin not only plays a role in regulating short-term feeding, but it also regulates body weight over the long term. (See 'Ghrelin and disease' below.)

Elevated fasting levels of ghrelin are associated with activation of reward centers in the hypothalamus, amygdala, and prefrontal cortex, indicating that food consumption is more complicated than hunger and satiety (figure 1) [30].

Adiposity — In obese subjects, normal postprandial suppression of ghrelin is impaired [31]. In addition, ghrelin can induce adiposity that is sustained as long as ghrelin levels are elevated, counteract decreases in energy storage, and prevent starvation and cachexia. Thus, ghrelin is the first hormone to be discovered that acts as a signal of starvation, and it is likely involved in the long-term regulation of body mass [32].

Neuropeptide Y — In the central nervous system, ghrelin activates NPY and AgRP-producing neurons in the arcuate nucleus of the hypothalamus, which is an important region of the brain involved in the regulation of feeding [4,33]. (See "Obesity: Genetic contribution and pathophysiology".)

In addition to the pituitary and hypothalamus, the ghrelin hormone secretagogue receptor GHSR1a is expressed in various other regions within the brain including the cerebral cortex, hippocampus, ventral tegmental region, and substantia nigra [34]. Accordingly, ghrelin has been shown to affect numerous higher brain functions, such as memory, sleep, reward-seeking behavior, anxiety, and mood [35-37].

Gastric motility — Like motilin, ghrelin stimulates gastric contraction and enhances stomach emptying (figure 1). It also potentiates phase III-like contractile activity of the stomach and duodenum. These effects are mediated by vagal cholinergic pathways. In murine models, ghrelin has been shown to depolarize interstitial cells of Cajal that regulate gastrointestinal pacemaker function [38]. The prokinetic effects of ghrelin oppose those of other gastrointestinal peptides, such as cholecystokinin, which serve as satiety signals.

Immune function — Some evidence suggests that ghrelin may have direct anti-inflammatory effects [39,40]. In one report, ghrelin receptors expressed on human T cells and monocytes mediated the inhibition of proinflammatory and anorectic cytokines, including interleukin-1-beta and tumor necrosis factor-alpha [40].

Bone formation and body mass — Growth hormone is known to promote bone formation, raising the possibility that ghrelin may also affect bone metabolism. Interestingly, osteoblasts have been shown to express GHSR1a, and ghrelin stimulates both osteoblast cell proliferation and differentiation [41]. Moreover, ghrelin was shown to increase bone mineral density (BMD) in both normal and growth hormone-deficient rats. In healthy, adolescent girls and in those with anorexia nervosa (a disorder characterized by higher-than-normal ghrelin secretion), serum ghrelin concentrations appear to be an independent predictor of BMD [42].

A decrease in growth hormone secretion accompanies aging and may contribute to the sarcopenia that develops in older adults. Ghrelin agonists have been shown to enhance pulsatile growth hormone secretion and increase non-fat body mass [43].

Growth hormone axis — Defects in GHSR have been associated with short stature, and the GHSR locus appears to be a site of genetic variation for height [44,45].

Thermoregulation – In mammals, body temperature is highly regulated. One of the hormones that affects thermoregulation is ghrelin. Ghrelin decreases body temperature under normal and cool conditions; however, desacyl-ghrelin decreases body temperature under hot conditions [46].

Behavior – Ghrelin signaling pathways appear to be involved in addictive behaviors. In rodents, GHSR antagonists have been shown to reduce alcohol drinking, including seeking and relapse behaviors [47].

Islet function — In pancreatic islets, GHSR1a is expressed primarily on D cells, indicating that ghrelin inhibits insulin and glucagon secretion indirectly through somatostatin [48]. Consistent with its receptor expression, ghrelin inhibits glucose-stimulated insulin secretion [49].

GHRELIN AND DISEASE

Obesity — Ghrelin levels are low in obesity and are inversely associated with weight gain and insulin resistance. Conversely, increased ghrelin levels are associated with low-calorie diets, exercise, anorexia, and cachexia. Ghrelin levels are low in obese individuals who binge eat, suggesting that ghrelin is a consequence rather than a cause of this condition [50]. (See "Obesity: Genetic contribution and pathophysiology", section on 'Stimulators of food intake'.)

Gastric bypass surgery — Ghrelin levels are lower after some bariatric procedures. Gastric bypass surgery is a commonly used and successful treatment for patients with obesity. This operation creates a small gastric pouch drained by an intestinal limb so that only a small gastric reservoir remains and ingested food bypasses most of the stomach, all of the duodenum, and much of the jejunum. Gastric bypass patients exhibit different plasma ghrelin profiles [51].

They lack the premeal increase in plasma ghrelin that is seen in normal individuals and cumulative ghrelin secretion is much lower. Ghrelin levels are also reduced following sleeve gastrectomy [52]. This lack of ghrelin response may be one of the mechanisms contributing to the overall effectiveness and negative energy balance seen after surgery that reduces food exposure in the stomach. (See "Bariatric surgery for management of obesity: Indications and preoperative preparation".)

Reduced ghrelin secretion following gastric bypass surgery may improve glucose tolerance. Under normal conditions, ghrelin stimulates secretion of insulin counterregulatory hormones, suppresses adiponectin secretion, and inhibits insulin secretion. These negative actions on insulin secretion are diminished when ghrelin release is impaired [53].

Prader-Willi syndrome — Prader-Willi syndrome is a congenital obesity syndrome that is characterized by severe hyperphagia, growth hormone deficiency, hypogonadism, dysmorphic features, and cognitive impairment. The genetic basis lies in the functional loss of several paternally expressed genes in an imprinted domain on chromosome 15 [54]. (See "Prader-Willi syndrome: Management" and "Prader-Willi syndrome: Clinical features and diagnosis".)

While obesity is usually accompanied by low ghrelin levels, that which is associated with Prader-Willi syndrome has high circulating ghrelin levels that do not decline after a meal [55,56]. The levels of ghrelin in this syndrome are similar to those that would stimulate appetite and increase food intake in individuals receiving infusions of exogenous ghrelin; this suggests that abnormal ghrelin secretion may account for the hyperphagia in Prader-Willi syndrome [57]. It is not known whether the persistently elevated ghrelin levels are responsible for the deficient growth hormone secretion that may occur through desensitization, as has been seen with continuous growth hormone-releasing hormone (GHRH) stimulation of growth hormone release [58].

POTENTIAL CLINICAL USES — Due to its short circulating half-life, the therapeutic use of ghrelin itself is limited; however, several longer-acting analogues have been developed. The ghrelin mimetic drug macimorelin has been approved by the US Food and Drug Administration (FDA) for the diagnosis of growth hormone deficiency [59].

Given that ghrelin is a major signal for stimulating food intake, promoting positive energy balance, and weight gain, it is reasonable to expect that ghrelin receptor antagonists will block the orexigenic signals from the gastrointestinal tract to the brain and, therefore, may be effective antiobesity therapies. As a result, development of ghrelin antagonists is an area of intensive investigation on the part of pharmaceutical companies. It will be of particular interest to determine if interventions that lower circulating ghrelin levels or ghrelin receptor antagonists will effectively treat the hyperphagia and obesity of Prader-Willi syndrome.

Alternatively, ghrelin agonists may be useful to treat conditions of anorexia [60]. Based on the effects of ghrelin on food intake and its ability to inhibit production of anorectic proinflammatory cytokines, there may be a role for ghrelin in the treatment of cachexia [61-63]. The oral ghrelin agonist capromorelin has received veterinary approval for the treatment of unexpected weight loss in animals [64]. Advanced clinical trials are evaluating ghrelin agonists for the treatment of gastrointestinal motility disorders, including gastroparesis [65]. Although one macrocyclic ghrelin mimetic did not meet clinical endpoints in late-stage clinical trials, other small molecule ghrelin agonists may be more effective [66]. Finally, ghrelin mimetics may be useful to treat frailty in older adults [13]. It has been proposed that the elevated circulating levels of ghrelin that accompany fasting may contribute to the anti-aging effects observed with caloric restriction [67]. Therefore, it is possible that ghrelin mimetics may have effects beyond reducing frailty.

Based on its ability to prevent beta-amyloid accumulation in animal models, ghrelin has been proposed to protect against neurodegenerative conditions such as Alzheimer's disease [68].

SUMMARY

●Ghrelin – Ghrelin is a 28-amino-acid peptide that is the natural ligand for the growth hormone secretagogue receptor (GHSR). GHSR is a member of a G protein-coupled receptor (GPCR) subfamily that also includes receptors for motilin, neurotensin, and neuromedin U. (See 'Structure' above.)

The stomach is the richest source of ghrelin. Over 90 percent of the body's ghrelin is in the stomach and duodenum. Ghrelin is most abundant in the gastric fundus where it is produced in oxyntic glands by distinctive endocrine cells known as P/D1 cells. (See 'Tissue distribution' above.)

●Serum concentrations – Ghrelin concentrations in the blood increase during fasting and surge shortly before meals. Ghrelin levels decrease after eating. The suppressive effects of food on plasma ghrelin appear to be nutrient specific, with carbohydrates having the greatest effect, followed by protein and lipids. (See 'Secretion' above.)

●Effect on appetite – Ghrelin stimulates appetite and induces a positive energy balance that can lead to weight gain. Ghrelin is implicated in regulating mealtime hunger and meal initiation. Accumulating evidence indicates that ghrelin plays a central role in the neurohormonal regulation of food intake and energy homeostasis. (See 'Food intake and energy balance' above.)