GHRELIN IN HEALTH AND DISEASE

REVIEW

The Physiology and Potential Clinical Applications of Ghrelin, a Novel Peptide Hormone
NICHOLAS A. TRITOS, MD, DSC, AND EFI G. KOKKOTOU, MD, PHD
Ghrelin, a peptide hormone originally identified as the endogenous ligand of the growth hormone secretagogue receptor, is secreted primarily from the stomach and secondarily from the small intestine and colon. Ghrelin may also be expressed in the pancreatic islets, hypothalamus, pituitary, and several tissues in the periphery. The growth hormone secretagogue receptor is widely expressed, suggesting diverse physiologic roles for ghrelin. A growing body of evidence suggests that, in addition to its predictable effect on growth hormone secretion, ghrelin has an important role in the short-term regulation of appetite and the long-term regulation of energy balance and glucose homeostasis. Recent studies have implicated ghrelin in the regulation of gastrointestinal, cardiovascular, and immune function and have suggested a role for ghrelin in bone physiology. The identification of obestatin, a novel peptide hormone derived from the same gene as ghrelin, has recently added further complexity to ghrelin physiology. Obestatin appears to have actions opposite of ghrelin on energy homeostasis and gastrointestinal function. Despite the rapid progress, many questions remain unanswered, including the regulation of ghrelin and obestatin secretion, the downstream pathways that mediate their effects, and their precise physiologic endocrine and paracrine roles. This review presents data on ghrelin structure, expression, and function, with emphasis placed on human studies, highlighting areas that require future investigation and providing speculation about potential clinical applications of ghrelin agonists or antagonists.

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AgRP = agouti-related protein; GH = growth hormone; GHRH = growth hormonereleasing hormone; GHS = growth hormone secretagogue; NPY = neuropeptide Y

that mediates this response, termed the growth hormone secretagogue (GHS) receptor.4-8 Efforts to identify the endogenous ligand of the GHS receptor culminated in 1999 with the isolation of ghrelin from a stomach extract.1,3 In addition to its effect on GH secretion, ghrelin was subsequently found to have pleiotropic effects on appetite regulation and gastrointestinal and cardiovascular function. Obestatin, a second peptide derived from proteolytic cleavage of the ghrelin prohormone, was recently identified and shown to have effects opposite of ghrelin on energy homeostasis and gastrointestinal function.9 Obestatin binds to a previously orphan receptor (GPR39), which shares similarities with the GHS receptor.10 In this review, data are presented on ghrelin structure, expression, and function, with emphasis placed on human studies, highlighting areas that require future investigation and providing speculation about potential clinical applications of ghrelin agonists or antagonists. To compile this review article, we searched the literature by performing computerized MEDLINE searches (1976present) using the following keywords: ghrelin, obestatin, and growth hormone secretagogue (receptor). Articles were selected for inclusion based on our best judgment. STRUCTURE

he discovery of ghrelin has broadened our understanding of the interplay between the stomach and the brain and has shed new light on multiple physiologic processes, including the regulation of pituitary hormone secretion and energy homeostasis, gastrointestinal activity, and cardiovascular function, among others.1-3 The road that led to the discovery of ghrelin began close to 3 decades ago with the identification of several synthetic compounds, including both peptides and nonpeptides, with growth hormone (GH)releasing activity from pituitary somatotrophs in vitro and in vivo, followed by the cloning of the receptor
From the Department of Endocrinology, Lahey Clinic Medical Center,
Burlington, Mass, and Tufts Medical School, Boston, Mass (N.A.T.); and Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (E.G.K.). Individual reprints of this article are not available. Address correspondence to Nicholas A. Tritos, MD, DSc, Department of Endocrinology, Lahey Clinic Medical Center, 41 Mall Rd, Burlington, MA 01805 (e-mail: Nicholas.A.Tritos@lahey.org). 2006 Mayo Foundation for Medical Education and Research

Ghrelin is a 28-amino acid peptide with a unique posttranslational modification of the Ser3 residue to which an octanoyl moiety is esterified.1 The presence of a large hydrophobic group at Ser3 is essential for GHS receptor activation.11,12 There is also a nonacylated ghrelin form (des-acyl ghrelin) present in excess in plasma, whose physiologic role is not clear.13-15 After collection of blood specimens, EDTA and aprotinin should be added and the plasma fraction separated by centrifugation and immediately acidified before freezing at 70C to ensure stability of acylated ghrelin during storage.14 Ghrelin is highly conserved among mammals and has even been detected in chickens, fish, and bullfrogs, suggesting an important evolutionary role.1,2,16 Significant homology exists between ghrelin and motilin.17 The human preproghrelin gene is located on chromosome 3p25-26 and consists of 5 exons with 4 introns.18 Spliced ghrelin messenger RNA is translated to a 117amino acid preproghrelin precursor, which is subsequently
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GHRELIN IN HEALTH AND DISEASE

cleaved to yield ghrelin, some of which is further modified with the addition of the octanoyl moiety at Ser3.19 However, the precise enzymatic mechanisms that lead to ghrelin acylation have not been established. In addition, obestatin, a 23-amino acid peptide, has recently been identified in silico as a putative proteolytic fragment of the preproghrelin precursor and purified from rat stomach extracts.9 Obestatin is further modified by C terminal amidation and circulates in the rat plasma.9 However, it is currently not known whether obestatin is secreted from the human stomach as well. EXPRESSION Ghrelin is most abundantly expressed in specialized cells in the oxyntic glands of the gastric epithelium, originally termed X/A-like cells.15 Approximately 60% to 70% of circulating ghrelin is secreted by the stomach, and most of the remainder originates in the small intestine.15 It has been suggested that low-level ghrelin expression also occurs in several tissues outside the gut, including pancreatic islet cells, hypothalamus (arcuate nucleus and paraventricular neuron groups), pituitary, lung, adrenal cortex, kidney, and bone.1,20-26 This is still a matter of some controversy because tissue expression in these locations has generally been demonstrated using sensitive reverse transcriptasepolymerase chain reaction methods. Ghrelin immunoreactivity has also been found in the testis, including both Sertoli and Leydig cells, and the placenta (syncytiotrophoblast and cytotrophoblast).27-29 Low ghrelin levels have been measured in the cerebrospinal fluid by immunoassay, although the origin of this activity (brain vs peripheral tissues) is uncertain.30 REGULATION Plasma ghrelin levels exhibit a pronounced diurnal variation, are increased by fasting and before meals and at night, and are rapidly (within <1 hour) suppressed by food intake, particularly by high-calorie or high-carbohydrate meals.31-35 In contrast, systemic obestatin levels do not change with fasting, at least in experimental animals.9 The underlying mechanisms that mediate suppression of systemic ghrelin secretion by food are not known. Postgastric or postabsorptive mechanisms have been implicated in studies performed in experimental animals and humans.32,36 In addition, both fasting plasma and cerebrospinal fluid ghrelin levels are negatively associated with body adiposity, supporting a role of ghrelin in the long-term regulation of energy homeostasis (see subsequent discussion).30,37-39 Cholinergic stimulation leads to increased plasma ghrelin levels.40 Combined growth hormonereleasing hor654 Mayo Clin Proc.

mone (GHRH)arginine administration similarly leads to increased plasma ghrelin levels.41 Estrogen and recombinant human insulin-like growth factor I increase systemic ghrelin levels in patients with anorexia nervosa.42 In contrast, oral or intravenous glucose, insulin, glucagon, GH, and somatostatin suppress systemic ghrelin levels.39,43-49 Taken together with the stimulatory effect of ghrelin on GH secretion, the suppressive effect of GH on ghrelin expression in the stomach and systemic ghrelin levels may suggest the presence of a negative feedback loop mechanism between the stomach and the pituitary. Alternatively, it is possible that common factors may regulate both ghrelin and GH secretion in a reciprocal fashion.50-52 Short-term infusions of peptide YY, oxyntomodulin, and urocortin, all putative appetite-suppressing peptides, lead to a decrease in plasma ghrelin levels.53-55 In contrast, leptin administration does not appear to have an effect on plasma ghrelin.56 Low systemic ghrelin levels have been reported in untreated hyperthyroidism, in male hypogonadism, in the polycystic ovary syndrome, in the presence of Helicobacter pyloriinduced gastritis, or after total gastrectomy.57-63 However, the pathophysiologic implications of these findings have not been clearly elucidated. The factors involved in the regulation of systemic ghrelin levels and the underlying mechanisms have not been fully characterized. Clearly, several areas of controversy exist. Insulin appears to suppress ghrelin secretion at high concentrations in humans, but the physiologic relevance of these findings is less certain.43,44 Insulin may be required for maximal postprandial suppression of serum ghrelin levels, as suggested by some but not all studies.64-66 Data on regulation of systemic ghrelin levels are given in Table 1. RECEPTOR AND EFFECTOR MECHANISMS The ghrelin and obestatin receptors share significant homology and belong to the ghrelin-motilin receptor subfamily of 7 transmembrane G proteincoupled receptors.8,10 The GHS receptor has an essential role in the transduction of the effects of acylated ghrelin on GH secretion and energy homeostasis.8,12,67 This receptor is well conserved among several species, including mammals, chickens, and fish.68,69 The GHS receptor is expressed in the pituitary gland, the hypothalamus (arcuate and ventromedial nucleus), the hippocampus, the raphe nuclei, and the substantia nigra.8,70 In addition, low-level expression has been demonstrated in a wide variety of peripheral tissues, including the gastrointestinal tract, liver, pancreas, heart, lung, kidney, adipose tissue, and even immune cells, suggesting diverse physiologic roles for ghrelin.8,70,71
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GHRELIN IN HEALTH AND DISEASE

The full-length active GHS receptor is termed GHS-1a, whereas a truncated, apparently inactive, GHS receptor isoform is termed GHS-1b.8 The GHS-1a receptor has some ligand-independent constitutive activity and engages primarily Gq/phospholipase C pathways.8,72-74 In addition, adenosine acts as a partial agonist on the GHS-1a receptor, engaging Gs/protein kinase A pathways.75-77 Because nonacylated ghrelin does not activate GHS-1a, it has been suggested that nonacylated ghrelin binds and activates a novel receptor distinct from GHS, which has not yet been identified.78,79 In addition, the existence of a second receptor for acylated ghrelin has been proposed based on circumstantial data but also remains to be demonstrated.80,81 The obestatin receptor, a previously orphan receptor (GPR39), is ubiquitous in distribution, including expression in the liver, hypothalamus, heart, and pancreas, with the highest levels detected in the gastrointestinal tract and the pituitary.9 PHYSIOLOGIC FUNCTIONS REGULATION OF PITUITARY HORMONE SECRETION Ghrelin derives its name from its stimulatory effect on GH secretion (ghre, proto Indo-European word root for grow), as demonstrated in vitro and in human and animal studies.1,82-87 Ghrelin has a direct effect on pituitary somatotroph cells in vitro and acts synergistically with GHRH to stimulate GH secretion.1,82,84 Ghrelin may have direct hypothalamic effects and may stimulate vagal afferents to further induce GH secretion.88,89 In high doses, ghrelin may also stimulate prolactin, corticotropin, and cortisol secretion in humans.83,84,87 Animal studies that involve genetic ablation of either the ghrelin gene or the GHS receptor suggest that neither ghrelin nor its classic GHS receptor is required for growth.67,90 The presence of compensatory mechanisms cannot be ruled out as an explanation for these findings. The relevance of these observations to human physiology is uncertain and is being challenged by the recent report of familial short stature in association with a GHS receptor mutation, leading to decreased ghrelin binding to the mutant receptor.91 These data suggest that ghrelin signaling may be essential for normal growth in humans. In contrast to ghrelin, obestatin apparently lacks any effect on GH secretion in vitro.9 However, the high expression of the obestatin receptor (GPR39) in the pituitary may implicate obestatin in the regulation of pituitary hormone secretion and suggests the need for further investigation of obestatin effects on pituitary function. REGULATION OF ENERGY HOMEOSTASIS Several lines of evidence suggest that ghrelin has an important role in the regulation of meal initiation. As previously
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TABLE 1. States and Factors Associated With Changes in Systemic Ghrelin Levels Increased systemic ghrelin Preprandial or fasting state Weight loss achieved through diet and/or exercise Prader-Willi syndrome Anorexia or eating disorders Cachexia (cardiac or malignancy associated) Ghrelin-secreting neoplasm Cholinergic stimulation Growth hormonereleasing hormonearginine Estrogen (in anorexia nervosa) Insulin-like growth factor I (in anorexia nervosa) Decreased systemic ghrelin Postprandial state Weight gain Gastric bypass surgery Total gastrectomy Helicobacter pyloriinduced gastritis Hyperthyroidism Male hypogonadism; polycystic ovary syndrome Glucose Insulin Glucagon Growth hormone Somatostatin Peptide YY Oxyntomodulin Urocortin

noted, systemic ghrelin levels increase before meals and decrease postprandially within less than 1 hour from meal initiation.31,33,34,92,93 Prandial changes in plasma ghrelin levels occur in association with changes in hunger scores, even when external cues related to time of day have been removed from the environment.94 In experimental animals, central or systemic ghrelin administration stimulates food intake.95-97 In contrast, central or systemic obestatin administration decreases food intake in experimental animals.9 In humans, ghrelin infusion that leads to an increase in plasma ghrelin to preprandial levels stimulates hunger and spontaneous food intake.98 Subcutaneous ghrelin administration also stimulates appetite and food intake in obese and lean humans.99,100 Postprandial suppression of serum ghrelin is less robust in obese individuals, possibly contributing to the pathogenesis of obesity.33,34,101,102 In addition to its putative role as a short-term signal that regulates meal initiation and satiety, ghrelin appears to have a role as a long-term signal of nutritional status opposite to that of leptin. Systemic ghrelin levels are negatively associated with body adiposity and increase with weight loss induced by low-calorie diet, exercise, anorexia nervosa, or cachexia as a result of organ failure (cardiac, pulmonary, renal, or hepatic) or malignancy.34,37,39,101,103-109 Weight gain induced by high-fat diet, therapy for anorexia nervosa, or glucocorticoid administration leads to decreased systemic ghrelin levels.106,109,110 Long-term ghrelin administration leads to weight gain in experimental animals by stimulating food intake, decreasing energy expenditure and spontaneous activity, and promoting adipogenesis.79,95-97,111,112 In contrast, obestatin administration attenuates weight gain in experimental ani www.mayoclinicproceedings.com 655

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mals and opposes ghrelin effects.9 Genetic ablation of either the ghrelin gene or the GHS receptor does not lead to obvious leanness in experimental animals under basal conditions, although the deletion of the ghrelin gene may lead to a decline in respiratory quotient and a trend toward leanness on high-fat diet.67,90,113 It is possible that compensatory mechanisms may mitigate the lack of ghrelin signaling in these studies. Alternatively, the phenotype that results from ghrelin gene ablation may be confounded by the absence of obestatin. Several human studies support the hypothesis that ghrelin has an important role in the long-term regulation of energy homeostasis. In humans, ghrelin gene polymorphisms have been associated with variations in body adiposity.114,115 Patients with the Prader-Willi syndrome have very high systemic ghrelin levels, hyperphagia, and morbid obesity, suggesting a role of ghrelin in the pathogenesis of obesity in this condition.116-120 A patient with a malignant tumor that secreted ghrelin remained obese and did not become anorexic until developing metastatic disease, a finding consistent with a role for ghrelin as an anabolic hormone.121 Systemic ghrelin levels decrease in morbidly obese patients after gastric bypass surgery, suggesting that ghrelin may be involved in the mechanisms that lead to weight loss.34 This observation has been confirmed in most, but not all, subsequent studies of gastric bypass patients.101,122-132 Although further studies are needed to explain the discrepancy, most data are consistent with the hypothesis that changes in systemic ghrelin levels may be involved in the mechanisms that lead to weight loss after gastric bypass surgery. The pathways that mediate ghrelin effects on appetite and energy expenditure have not been fully elucidated. In experimental animals, ghrelin is more potent in stimulating appetite when administered centrally rather than systemically.95-97 Ghrelin leads to c-fos activation in arcuate hypothalamic neurons that express the GHS receptor (as well as the leptin receptor) and are known to have an important role in energy homeostasis.95,133 The expression of appetitestimulating peptides neuropeptide Y (NPY) and agouti-related protein (AgRP) is increased by ghrelin in the arcuate hypothalamic nucleus.133,134 The effect of ghrelin on food intake is inhibited in mice with genetic ablation of NPY and AgRP genes, suggesting that neurons that express these peptides have an important role in mediating ghrelin actions.135 The arcuate hypothalamic nucleus is relatively accessible to systemic peptides as a consequence of its proximity to the median eminence, supporting the notion of direct ghrelin action in the hypothalamus. In addition, locally synthesized hypothalamic ghrelin may have an important role in appetite regulation.23,24 Both human and animal studies suggest that the appetite-stimulating effects of ghrelin are inhibited
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by vagotomy, indicating that ghrelin may also have direct effects on vagal afferent activity.89,136 REGULATION OF GASTROINTESTINAL MOTILITY AND SECRETION Additional studies suggest that ghrelin leads to increased gastrointestinal motility and (possibly) increased gastric acid secretion, which may be physiologically relevant in preparing the gastrointestinal tract to process food.137-142 Preliminary data suggest that obestatin decreases both stomach emptying and jejunum contractility.9 REGULATION OF GLUCOSE HOMEOSTASIS Available data suggest a negative association between systemic ghrelin and insulin levels.33,37 Ghrelin inhibits insulin secretion both in vitro and in most human or animal studies.143-147 However, other studies have suggested that ghrelin may stimulate insulin secretion in certain paradigms.148 In addition, it is not clear whether endocrine or paracrine effects of ghrelin are more physiologically relevant in the regulation of insulin secretion. Ghrelin inhibits insulin effects on glycogen synthesis and gluconeogenesis in vitro.149 Ghrelin may also inhibit secretion of the insulin-sensitizing protein adiponectin from adipocytes and stimulate secretion of the counterregulatory hormones, including GH, cortisol, epinephrine, and (possibly) glucagon.87,150,151 More studies are needed to fully elucidate the precise physiologic role of ghrelin on the regulation of glucose homeostasis. REGULATION OF CARDIOVASCULAR FUNCTION Human data suggest an association between systemic ghrelin levels and cardiovascular indexes.152 In addition, ghrelin infusion has acute hemodynamic effects in healthy human volunteers, increasing cardiac index and stroke volume and decreasing blood pressure.153 In an animal model of congestive heart failure, longterm ghrelin administration led to beneficial hemodynamic effects, increasing cardiac output, preventing left ventricular remodeling, and decreasing blood pressure.154 Salutary hemodynamic effects were also observed in patients with congestive heart failure who were administered short-term ghrelin infusions.155 The finding of GHS receptors in the heart and blood vessels supports the hypothesis that ghrelin has direct effects on the cardiovascular system. Ghrelin may inhibit inflammatory pathways in human endothelial cells, including nuclear factor kB.156 However, the role of ghrelin and its analogues in the pathogenesis and treatment of atherosclerosis remains to be established. OTHER GHRELIN EFFECTS Ghrelin and its agonists may also modulate immune function by enhancing immune cell proliferation and inhibiting
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secretion of proinflammatory cytokines from immune cells.157-159 In contrast, a recent study160 suggested that both ghrelin and its receptor are up-regulated in experimental colonic inflammation. Stimulation of colonic epithelial cells with ghrelin led to nuclear factor kB activation and stimulation of interleukin 8 expression.160 Thus, ghrelin may have tissue-specific effects that can be either antiinflammatory or proinflammatory. Several other effects have been attributed to ghrelin. Ghrelin may directly influence osteoblast growth.22 Indices of systemic ghrelin secretion show a correlation with bone mineral density in healthy adolescents.161 Furthermore, decreased systemic ghrelin secretion may lead to osteopenia after gastrectomy.162,163 The role of ghrelin in the pathogenesis and treatment of bone metabolic disorders requires further evaluation. Nonacylated ghrelin may have specific effects on glucose homeostasis, lipolysis, adipogenesis, cell apoptosis, and cardiovascular function.78,79,164-166 Because nonacylated ghrelin does not engage the GHS receptor, a currently unidentified receptor may exist that mediates nonacylated ghrelin effects.78,79 FUTURE DIRECTIONS The discovery of ghrelin has provided a wealth of novel information on the interrelationships between stomach and brain and expanded our understanding of the regulation of GH secretion, energy and glucose homeostasis, and gastrointestinal and cardiovascular function. In addition to its possible pathophysiologic role in growth disorders, ghrelin (or its analogues) may have a role in the diagnosis and treatment of relevant conditions. In combination with GHRH, administration of GHSs (GHS agonists), such as GHRP-6, may be useful in the diagnosis of GH deficiency.167 Further studies are needed to evaluate the potential role of ghrelin in the diagnosis of hypopituitarism, including GH deficiency. In addition, the efficacy of GHSs as therapies for GH deficiency requires further investigation (Table 2). Studies of ghrelin analogues and antagonists not only will help elucidate their role in the regulation of energy homeostasis but also may lead to novel therapies for conditions associated with weight loss (including anorexia and bulimia, disease-associated cachexia, and age-related wasting) and weight gain (simple obesity and Prader-Willi syndrome), respectively (Table 2).168 Ghrelin may increase gastrointestinal motility in gastroparesis.169 However, the efficacy and safety of ghrelin or other GHSs in conditions of decreased gastrointestinal motility, including gastroparesis and ileus, remain to be conclusively established (Table 2). Similarly, the role of ghreMayo Clin Proc.

TABLE 2. Clinical Conditions in Which Ghrelin Agonists or Antagonists May Have Therapeutic Potential* Ghrelin agonists Growth hormone deficiency (therapy) Hypopituitarism or growth hormone deficiency (diagnosis) Cachexia (associated with aging, gastrectomy, chronic organ insufficiency, malignancy, or HIV infection) Anorexia or eating disorders Dilated cardiomyopathy or CHF Atherosclerosis Gastroparesis Ileus Osteoporosis or metabolic bone disease Ghrelin antagonists Simple obesity Prader-Willi syndrome

*Conditions in which ghrelin agonists may serve as useful diagnostic agents are indicated. CHF = congestive heart failure; HIV = human immunodeficiency virus.

lin in the treatment of congestive heart failure requires further study (Table 2). Despite the rapid advances in the ghrelin field, many issues remain unresolved, including regulation of ghrelin secretion, the role of nonacylated ghrelin, ghrelin receptor(s), ghrelin signaling, and downstream pathways. Furthermore, the precise physiologic role of ghrelin acting in an endocrine and paracrine fashion must be established, and the therapeutic potential of ghrelin agonists and antagonists remains to be fruitfully exploited. Data on the expression, regulation, and physiologic role of obestatin in humans are currently not available and will likely be the focus of several investigations. It is hoped that the substantial interest generated in these unique peptide hormones will soon lead to resolution of these important issues.

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