Advertisement
Mayo Clinic Proceedings Home

The Physiology and Potential Clinical Applications of Ghrelin, a Novel Peptide Hormone

      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.
      AgRP (agouti-related protein), GH (growth hormone), GHRH (growth hormone-releasing hormone), GHS (growth hormone secretagogue), NPY (neuropeptide Y)
      The 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.
      • Kojima M
      • Hosoda H
      • Date Y
      • Nakazato M
      • Matsuo H
      • Kangawa K
      Ghrelin is a growth-hormone-releasing acylated peptide from stomach.
      • Kojima M
      • Hosoda H
      • Kangawa K
      Clinical endocrinology and metabolism: ghrelin, a novel growth-hormone-releasing and appetite-stimulating peptide from stomach.
      • Kojima M
      • Hosoda H
      • Matsuo H
      • Kangawa K
      Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor.
      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 that mediates this response, termed the growth hormone secretagogue (GHS) receptor.
      • Bowers CY
      • Momany F
      • Reynolds GA
      • Chang D
      • Hong A
      • Chang K
      Structure-activity relationships of a synthetic pentapeptide that specifically releases growth hormone in vitro.
      • Bowers CY
      • Momany FA
      • Reynolds GA
      • Hong A
      On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone.
      • Smith RG
      • Cheng K
      • Schoen WR
      • et al.
      A nonpeptidyl growth hormone secretagogue.
      • Cheng K
      • Chan WW
      • Butler B
      • et al.
      Stimulation of growth hormone release from rat primary pituitary cells by L-692,429, a novel non-peptidyl GH secretagogue.
      • Howard AD
      • Feighner SD
      • Cully DF
      • et al.
      A receptor in pituitary and hypothalamus that functions in growth hormone release.
      Efforts to identify the endogenous ligand of the GHS receptor culminated in 1999 with the isolation of ghrelin from a stomach extract.
      • Kojima M
      • Hosoda H
      • Date Y
      • Nakazato M
      • Matsuo H
      • Kangawa K
      Ghrelin is a growth-hormone-releasing acylated peptide from stomach.
      • Kojima M
      • Hosoda H
      • Matsuo H
      • Kangawa K
      Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor.
      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.
      • Zhang JV
      • Ren PG
      • Avsian-Kretchmer O
      • et al.
      Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake.
      Obestatin binds to a previously orphan receptor (GPR39), which shares similarities with the GHS receptor.
      • McKee KK
      • Tan CP
      • Palyha OC
      • et al.
      Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors.
      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 (1976-present) using the following keywords: ghrelin, obestatin, and growth hormone secretagogue (receptor). Articles were selected for inclusion based on our best judgment.

      STRUCTURE

      Ghrelin is a 28-amino acid peptide with a unique posttranslational modification of the Ser3 residue to which an octanoyl moiety is esterified.
      • Kojima M
      • Hosoda H
      • Date Y
      • Nakazato M
      • Matsuo H
      • Kangawa K
      Ghrelin is a growth-hormone-releasing acylated peptide from stomach.
      The presence of a large hydrophobic group at Ser3 is essential for GHS receptor activation.
      • Matsumoto M
      • Hosoda H
      • Kitajima Y
      • et al.
      Structure-activity relationship of ghrelin: pharmacological study of ghrelin peptides.
      • Bednarek MA
      • Feighner SD
      • Pong SS
      • et al.
      Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a.
      There is also a nonacylated ghrelin form (des-acyl ghrelin) present in excess in plasma, whose physiologic role is not clear.
      • Akamizu T
      • Shinomiya T
      • Irako T
      • et al.
      Separate measurement of plasma levels of acylated and desacyl ghrelin in healthy subjects using a new direct ELISA assay.
      • Hosoda H
      • Kojima M
      • Matsuo H
      • Kangawa K
      Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue.
      • Date Y
      • Kojima M
      • Hosoda H
      • et al.
      Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans.
      After collection of blood specimens, EDTA and aprotinin should be added and the plasma fraction separated by centrifugation and immediately acidified before freezing at -70°C to ensure stability of acylated ghrelin during storage.
      • Hosoda H
      • Kojima M
      • Matsuo H
      • Kangawa K
      Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue.
      Ghrelin is highly conserved among mammals and has even been detected in chickens, fish, and bullfrogs, suggesting an important evolutionary role.
      • Kojima M
      • Hosoda H
      • Date Y
      • Nakazato M
      • Matsuo H
      • Kangawa K
      Ghrelin is a growth-hormone-releasing acylated peptide from stomach.
      • Kojima M
      • Hosoda H
      • Kangawa K
      Clinical endocrinology and metabolism: ghrelin, a novel growth-hormone-releasing and appetite-stimulating peptide from stomach.
      • Kojima M
      • Kangawa K
      Ghrelin: structure and function.
      Significant homology exists between ghrelin and motilin.
      • Folwaczny C
      • Chang JK
      • Tschop M
      Ghrelin and motilin: two sides of one coin?.
      The human preproghrelin gene is located on chromosome 3p25-26 and consists of 5 exons with 4 introns.
      • Kanamoto N
      • Akamizu T
      • Tagami T
      • et al.
      Genomic structure and characterization of the 5′-flanking region of the human ghrelin gene.
      Spliced ghrelin messenger RNA is translated to a 117-amino acid preproghrelin precursor, which is subsequently cleaved to yield ghrelin, some of which is further modified with the addition of the octanoyl moiety at Ser3.
      • Hosoda H
      • Kojima M
      • Mizushima T
      • Shimizu S
      • Kangawa K
      Structural divergence of human ghrelin: identification of multiple ghrelin-derived molecules produced by post-translational processing.
      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.
      • Zhang JV
      • Ren PG
      • Avsian-Kretchmer O
      • et al.
      Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake.
      Obestatin is further modified by C terminal amidation and circulates in the rat plasma.
      • Zhang JV
      • Ren PG
      • Avsian-Kretchmer O
      • et al.
      Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake.
      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.
      • Date Y
      • Kojima M
      • Hosoda H
      • et al.
      Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans.
      Approximately 60% to 70% of circulating ghrelin is secreted by the stomach, and most of the remainder originates in the small intestine.
      • Date Y
      • Kojima M
      • Hosoda H
      • et al.
      Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans.
      It has been suggested that low-level ghrelin expression also occurs in several tissues outside the gut, including ɛ-pancreatic islet cells, hypothalamus (arcuate nucleus and paraventricular neuron groups), pituitary, lung, adrenal cortex, kidney, and bone.
      • Kojima M
      • Hosoda H
      • Date Y
      • Nakazato M
      • Matsuo H
      • Kangawa K
      Ghrelin is a growth-hormone-releasing acylated peptide from stomach.
      • Prado CL
      • Pugh-Bernard AE
      • Elghazi L
      • Sosa-Pineda B
      • Sussel L
      Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development.
      • Wierup N
      • Yang S
      • McEvilly RJ
      • Mulder H
      • Sundler F
      Ghrelin is expressed in a novel endocrine cell type in developing rat islets and inhibits insulin secretion from INS-1 (832/13) cells.
      • Fukushima N
      • Hanada R
      • Teranishi H
      • et al.
      Ghrelin directly regulates bone formation.
      • Cowley MA
      • Smith RG
      • Diano S
      • et al.
      The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis.
      • Lu S
      • Guan JL
      • Wang QP
      • et al.
      Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus.
      • Gnanapavan S
      • Kola B
      • Bustin SA
      • et al.
      The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans.
      • Mozid AM
      • Tringali G
      • Forsling ML
      • et al.
      Ghrelin is released from rat hypothalamic explants and stimulates corticotrophin-releasing hormone and arginine-vasopressin.
      This is still a matter of some controversy because tissue expression in these locations has generally been demonstrated using sensitive reverse transcriptase-polymerase chain reaction methods.
      Ghrelin immunoreactivity has also been found in the testis, including both Sertoli and Leydig cells, and the placenta (syncytiotrophoblast and cytotrophoblast).
      • Barreiro ML
      • Gaytan F
      • Caminos JE
      • et al.
      Cellular location and hormonal regulation of ghrelin expression in rat testis.
      • Tena-Sempere M
      • Barreiro ML
      • Gonzalez LC
      • et al.
      Novel expression and functional role of ghrelin in rat testis.
      • Gualillo O
      • Caminos J
      • Blanco M
      • et al.
      Ghrelin, a novel placental-derived hormone.
      Low ghrelin levels have been measured in the cerebrospinal fluid by immunoassay, although the origin of this activity (brain vs peripheral tissues) is uncertain.
      • Tritos NA
      • Kokkinos A
      • Lampadariou E
      • Alexiou E
      • Katsilambros N
      • Maratos-Flier E
      Cerebrospinal fluid ghrelin is negatively associated with body mass index.

      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.
      • Tschop M
      • Wawarta R
      • Riepl RL
      • et al.
      Post-prandial decrease of circulating human ghrelin levels.
      • Overduin J
      • Frayo RS
      • Grill HJ
      • Kaplan JM
      • Cummings DE
      Role of the duodenum and macronutrient type in ghrelin regulation.
      • Cummings DE
      • Purnell JQ
      • Frayo RS
      • Schmidova K
      • Wisse BE
      • Weigle DS
      A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans.
      • Cummings DE
      • Weigle DS
      • Frayo RS
      • et al.
      Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery.
      • Weigle DS
      • Cummings DE
      • Newby PD
      • et al.
      Roles of leptin and ghrelin in the loss of body weight caused by a low fat, high carbohydrate diet.
      In contrast, systemic obestatin levels do not change with fasting, at least in experimental animals.
      • Zhang JV
      • Ren PG
      • Avsian-Kretchmer O
      • et al.
      Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake.
      The underlying mechanisms that mediate suppression of systemic ghrelin secretion by food are not known. Post-gastric or postabsorptive mechanisms have been implicated in studies performed in experimental animals and humans.
      • Overduin J
      • Frayo RS
      • Grill HJ
      • Kaplan JM
      • Cummings DE
      Role of the duodenum and macronutrient type in ghrelin regulation.
      • Blom WA
      • Lluch A
      • Vinoy S
      • et al.
      Effects of gastric emptying on the postprandial ghrelin response.
      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).
      • Tritos NA
      • Kokkinos A
      • Lampadariou E
      • Alexiou E
      • Katsilambros N
      • Maratos-Flier E
      Cerebrospinal fluid ghrelin is negatively associated with body mass index.
      • Tschop M
      • Weyer C
      • Tataranni PA
      • Devanarayan V
      • Ravussin E
      • Heiman ML
      Circulating ghrelin levels are decreased in human obesity.
      • Cummings DE
      • Shannon MH
      Roles for ghrelin in the regulation of appetite and body weight.
      • Shiiya T
      • Nakazato M
      • Mizuta M
      • et al.
      Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion.
      Cholinergic stimulation leads to increased plasma ghrelin levels.
      • Broglio F
      • Gottero C
      • Van Koetsveld P
      • et al.
      Acetylcholine regulates ghrelin secretion in humans.
      Combined growth hormone-releasing hormone (GHRH)-arginine administration similarly leads to increased plasma ghrelin levels.
      • Koutkia P
      • Canavan B
      • Breu J
      • Johnson ML
      • Grinspoon SK
      Nocturnal ghrelin pulsatility and response to growth hormone secretagogues in healthy men.
      Estrogen and recombinant human insulin-like growth factor I increase systemic ghrelin levels in patients with anorexia nervosa.
      • Grinspoon S
      • Miller KK
      • Herzog DB
      • Grieco KA
      • Klibanski A
      Effects of estrogen and recombinant human insulin-like growth factor-I on ghrelin secretion in severe undernutrition.
      In contrast, oral or intravenous glucose, insulin, glucagon, GH, and somatostatin suppress systemic ghrelin levels.
      • Shiiya T
      • Nakazato M
      • Mizuta M
      • et al.
      Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion.
      • Anderwald C
      • Brabant G
      • Bernroider E
      • et al.
      Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients.
      • Mohlig M
      • Spranger J
      • Otto B
      • Ristow M
      • Tschop M
      • Pfeiffer AF
      Euglycemic hyperinsulinemia, but not lipid infusion, decreases circulating ghrelin levels in humans.
      • Arafat MA
      • Otto B
      • Rochlitz H
      • et al.
      Glucagon inhibits ghrelin secretion in humans.
      • Qi X
      • Reed J
      • Englander EW
      • Chandrashekar V
      • Bartke A
      • Greeley Jr, GH
      Evidence that growth hormone exerts a feedback effect on stomach ghrelin production and secretion.
      • Norrelund H
      • Hansen TK
      • Orskov H
      • et al.
      Ghrelin immunoreactivity in human plasma is suppressed by somatostatin.
      • Barkan AL
      • Dimaraki EV
      • Jessup SK
      • Symons KV
      • Ermolenko M
      • Jaffe CA
      Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels.
      • Broglio F
      • van Koetsveld P
      • Benso A
      • et al.
      Ghrelin secretion is inhibited by either somatostatin or cortistatin in humans.
      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.
      • Koutkia P
      • Schurgin S
      • Berry J
      • et al.
      Reciprocal changes in endogenous ghrelin and growth hormone during fasting in healthy women.
      • Misra M
      • Miller KK
      • Herzog DB
      • et al.
      Growth hormone and ghrelin responses to an oral glucose load in adolescent girls with anorexia nervosa and controls.
      • Misra M
      • Miller KK
      • Kuo K
      • et al.
      Secretory dynamics of ghrelin in adolescent girls with anorexia nervosa and healthy adolescents.
      Short-term infusions of peptide YY, oxyntomodulin, and urocortin, all putative appetite-suppressing peptides, lead to a decrease in plasma ghrelin levels.
      • Cohen MA
      • Ellis SM
      • Le Roux CW
      • et al.
      Oxyntomodulin suppresses appetite and reduces food intake in humans.
      • Davis ME
      • Pemberton CJ
      • Yandle TG
      • et al.
      Urocortin-1 infusion in normal humans.
      • Batterham RL
      • Cohen MA
      • Ellis SM
      • et al.
      Inhibition of food intake in obese subjects by peptide YY3-36.
      In contrast, leptin administration does not appear to have an effect on plasma ghrelin.
      • Chan JL
      • Bullen J
      • Lee JH
      • Yiannakouris N
      • Mantzoros CS
      Ghrelin levels are not regulated by recombinant leptin administration and/or three days of fasting in healthy subjects.
      Low systemic ghrelin levels have been reported in untreated hyperthyroidism, in male hypogonadism, in the polycystic ovary syndrome, in the presence of Helicobacter pylori-induced gastritis, or after total gastrectomy.
      • Riis AL
      • Hansen TK
      • Moller N
      • Weeke J
      • Jorgensen JO
      Hyperthyroidism is associated with suppressed circulating ghrelin levels.
      • Rojdmark S
      • Calissendorff J
      • Danielsson O
      • Brismar K
      Hunger-satiety signals in patients with Graves' thyrotoxicosis before, during, and after long-term pharmacological treatment.
      • Pagotto U
      • Gambineri A
      • Pelusi C
      • et al.
      Testosterone replacement therapy restores normal ghrelin in hypogonadal men.
      • Pagotto U
      • Gambineri A
      • Vicennati V
      • Heiman ML
      • Tschop M
      • Pasquali R
      Plasma ghrelin, obesity, and the polycystic ovary syndrome: correlation with insulin resistance and androgen levels.
      • Cummings DE
      Helicobacter pylori and ghrelin: interrelated players in body-weight regulation?.
      • Isomoto H
      • Ueno H
      • Saenko VA
      • et al.
      Impact of Helicobacter pylori infection on gastric and plasma ghrelin dynamics in humans.
      • Takachi K
      • Doki Y
      • Ishikawa O
      • et al.
      Postoperative ghrelin levels and delayed recovery from body weight loss after distal or total gastrectomy.
      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.
      • Anderwald C
      • Brabant G
      • Bernroider E
      • et al.
      Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients.
      • Mohlig M
      • Spranger J
      • Otto B
      • Ristow M
      • Tschop M
      • Pfeiffer AF
      Euglycemic hyperinsulinemia, but not lipid infusion, decreases circulating ghrelin levels in humans.
      Insulin may be required for maximal postprandial suppression of serum ghrelin levels, as suggested by some but not all studies.
      • Murdolo G
      • Lucidi P
      • Di Loreto C
      • et al.
      Insulin is required for prandial ghrelin suppression in humans.
      • Gelling RW
      • Overduin J
      • Morrison CD
      • et al.
      Effect of uncontrolled diabetes on plasma ghrelin concentrations and ghrelin-induced feeding.
      • Spranger J
      • Ristow M
      • Otto B
      • et al.
      Post-prandial decrease of human plasma ghrelin in the absence of insulin.
      Data on regulation of systemic ghrelin levels are given in Table 1.
      TABLE 1States and Factors Associated With Changes in Systemic Ghrelin Levels
      Increased systemic ghrelinDecreased systemic ghrelin
      Preprandial or fasting statePostprandial state
      Weight loss achieved through diet and/or exerciseWeight gain
      Prader-Willi syndromeGastric bypass surgery
      Anorexia or eating disordersTotal gastrectomy
      Cachexia (cardiac or malignancy associated)Helicobacter pylori—induced gastritis
      Ghrelin-secreting neoplasmHyperthyroidism
      Cholinergic stimulationMale hypogonadism; polycystic ovary syndrome
      Growth hormone–releasing hormone–arginineGlucose
      Estrogen (in anorexia nervosa)Insulin
      Insulin-like growth factor I (in anorexia nervosa)Glucagon
      Growth hormone
      Somatostatin
      Peptide YY
      Oxyntomodulin
      Urocortin

      RECEPTOR AND EFFECTOR MECHANISMS

      The ghrelin and obestatin receptors share significant homology and belong to the ghrelin-motilin receptor subfamily of 7 transmembrane G protein-coupled receptors.
      • Howard AD
      • Feighner SD
      • Cully DF
      • et al.
      A receptor in pituitary and hypothalamus that functions in growth hormone release.
      • McKee KK
      • Tan CP
      • Palyha OC
      • et al.
      Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors.
      The GHS receptor has an essential role in the transduction of the effects of acylated ghrelin on GH secretion and energy homeostasis.
      • Howard AD
      • Feighner SD
      • Cully DF
      • et al.
      A receptor in pituitary and hypothalamus that functions in growth hormone release.
      • Bednarek MA
      • Feighner SD
      • Pong SS
      • et al.
      Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a.
      • Sun Y
      • Wang P
      • Zheng H
      • Smith RG
      Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor.
      This receptor is well conserved among several species, including mammals, chickens, and fish.
      • Smith RG
      • Leonard R
      • Bailey AR
      • et al.
      Growth hormone secretagogue receptor family members and ligands.
      • Feighner SD
      • Tan CP
      • McKee KK
      • et al.
      Receptor for motilin identified in the human gastrointestinal system.
      The GHS receptor is expressed in the pituitary gland, the hypothalamus (arcuate and ventromedial nucleus), the hippocampus, the raphe nuclei, and the substantia nigra.
      • Howard AD
      • Feighner SD
      • Cully DF
      • et al.
      A receptor in pituitary and hypothalamus that functions in growth hormone release.
      • Guan XM
      • Yu H
      • Palyha OC
      • et al.
      Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues.
      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.
      • Howard AD
      • Feighner SD
      • Cully DF
      • et al.
      A receptor in pituitary and hypothalamus that functions in growth hormone release.
      • Guan XM
      • Yu H
      • Palyha OC
      • et al.
      Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues.
      • Hattori N
      • Saito T
      • Yagyu T
      • Jiang BH
      • Kitagawa K
      • Inagaki C
      GH, GH receptor, GH secretagogue receptor, and ghrelin expression in human T cells, B cells, and neutrophils.
      The full-length active GHS receptor is termed GHS-1a, whereas a truncated, apparently inactive, GHS receptor isoform is termed GHS-1b.
      • Howard AD
      • Feighner SD
      • Cully DF
      • et al.
      A receptor in pituitary and hypothalamus that functions in growth hormone release.
      The GHS-1a receptor has some ligand-independent constitutive activity and engages primarily Gq/phospholipase C pathways.
      • Howard AD
      • Feighner SD
      • Cully DF
      • et al.
      A receptor in pituitary and hypothalamus that functions in growth hormone release.
      • Kohno D
      • Gao HZ
      • Muroya S
      • Kikuyama S
      • Yada T
      Ghrelin directly interacts with neuropeptide-Y-containing neurons in the rat arcuate nucleus: Ca2+ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin.
      • Holst B
      • Cygankiewicz A
      • Jensen TH
      • Ankersen M
      • Schwartz TW
      High constitutive signaling of the ghrelin receptor—identification of a potent inverse agonist.
      • Holst B
      • Schwartz TW
      Constitutive ghrelin receptor activity as a signaling set-point in appetite regulation.
      In addition, adenosine acts as a partial agonist on the GHS-1a receptor, engaging Gs/protein kinase A pathways.
      • Tullin S
      • Hansen BS
      • Ankersen M
      • Moller J
      • Von Cappelen KA
      • Thim L
      Adenosine is an agonist of the growth hormone secretagogue receptor.
      • Carreira MC
      • Camina JP
      • Smith RG
      • Casanueva FF
      Agonist-specific coupling of growth hormone secretagogue receptor type 1a to different intracellular signaling systems: role of adenosine.
      • Smith RG
      • Griffin PR
      • Xu Y
      • et al.
      Adenosine: a partial agonist of the growth hormone secretagogue receptor.
      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.
      • Baldanzi G
      • Filigheddu N
      • Cutrupi S
      • et al.
      Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT.
      • van der Lely AJ
      • Tschop M
      • Heiman ML
      • Ghigo E
      Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin.
      In addition, the existence of a second receptor for acylated ghrelin has been proposed based on circumstantial data but also remains to be demonstrated.
      • Zhang W
      • Zhao L
      • Lin TR
      • et al.
      Inhibition of adipogenesis by ghrelin.
      • Halem HA
      • Taylor JE
      • Dong JZ
      • et al.
      Novel analogs of ghrelin: physiological and clinical implications.
      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.
      • Zhang JV
      • Ren PG
      • Avsian-Kretchmer O
      • et al.
      Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake.

      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.
      • Kojima M
      • Hosoda H
      • Date Y
      • Nakazato M
      • Matsuo H
      • Kangawa K
      Ghrelin is a growth-hormone-releasing acylated peptide from stomach.
      • Hataya Y
      • Akamizu T
      • Takaya K
      • et al.
      A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans.
      • Arvat E
      • Di Vito L
      • Broglio F
      • et al.
      Preliminary evidence that Ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans.
      • Arvat E
      • Maccario M
      • Di Vito L
      • et al.
      Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone.
      • Date Y
      • Murakami N
      • Kojima M
      • et al.
      Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats.
      • Peino R
      • Baldelli R
      • Rodriguez-Garcia J
      • et al.
      Ghrelin-induced growth hormone secretion in humans.
      • Takaya K
      • Ariyasu H
      • Kanamoto N
      • et al.
      Ghrelin strongly stimulates growth hormone release in humans.
      Ghrelin has a direct effect on pituitary somatotroph cells in vitro and acts synergistically with GHRH to stimulate GH secretion.
      • Kojima M
      • Hosoda H
      • Date Y
      • Nakazato M
      • Matsuo H
      • Kangawa K
      Ghrelin is a growth-hormone-releasing acylated peptide from stomach.
      • Hataya Y
      • Akamizu T
      • Takaya K
      • et al.
      A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans.
      • Arvat E
      • Maccario M
      • Di Vito L
      • et al.
      Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone.
      Ghrelin may have direct hypothalamic effects and may stimulate vagal afferents to further induce GH secretion.
      • Popovic V
      • Miljic D
      • Micic D
      • et al.
      Ghrelin main action on the regulation of growth hormone release is exerted at hypothalamic level.
      • Date Y
      • Murakami N
      • Toshinai K
      • et al.
      The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats.
      In high doses, ghrelin may also stimulate prolactin, corticotropin, and cortisol secretion in humans.
      • Arvat E
      • Di Vito L
      • Broglio F
      • et al.
      Preliminary evidence that Ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans.
      • Arvat E
      • Maccario M
      • Di Vito L
      • et al.
      Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone.
      • Takaya K
      • Ariyasu H
      • Kanamoto N
      • et al.
      Ghrelin strongly stimulates growth hormone release in humans.
      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.
      • Sun Y
      • Wang P
      • Zheng H
      • Smith RG
      Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor.
      • Sun Y
      • Ahmed S
      • Smith RG
      Deletion of ghrelin impairs neither growth nor appetite.
      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.
      • Pantel J
      • Legendre M
      • Cabrol S
      • et al.
      Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature.
      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.
      • Zhang JV
      • Ren PG
      • Avsian-Kretchmer O
      • et al.
      Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake.
      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 previouslynoted, systemic ghrelin levels increase before meals and decrease postprandially within less than 1 hour from meal initiation.
      • Tschop M
      • Wawarta R
      • Riepl RL
      • et al.
      Post-prandial decrease of circulating human ghrelin levels.
      • Cummings DE
      • Purnell JQ
      • Frayo RS
      • Schmidova K
      • Wisse BE
      • Weigle DS
      A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans.
      • Cummings DE
      • Weigle DS
      • Frayo RS
      • et al.
      Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery.
      • Sugino T
      • Hasegawa Y
      • Kikkawa Y
      • et al.
      A transient ghrelin surge occurs just before feeding in a scheduled meal-fed sheep.
      • Sugino T
      • Yamaura J
      • Yamagishi M
      • et al.
      A transient surge of ghrelin secretion before feeding is modified by different feeding regimens in sheep.
      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.
      • Cummings DE
      • Frayo RS
      • Marmonier C
      • Aubert R
      • Chapelot D
      Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues.
      In experimental animals, central or systemic ghrelin administration stimulates food intake.
      • Nakazato M
      • Murakami N
      • Date Y
      • et al.
      A role for ghrelin in the central regulation of feeding.
      • Tschop M
      • Smiley DL
      • Heiman ML
      Ghrelin induces adiposity in rodents.
      • Wren AM
      • Small CJ
      • Abbott CR
      • et al.
      Ghrelin causes hyperphagia and obesity in rats.
      In contrast, central or systemic obestatin administration decreases food intake in experimental animals.
      • Zhang JV
      • Ren PG
      • Avsian-Kretchmer O
      • et al.
      Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake.
      In humans, ghrelin infusion that leads to an increase in plasma ghrelin to preprandial levels stimulates hunger and spontaneous food intake.
      • Wren AM
      • Seal LJ
      • Cohen MA
      • et al.
      Ghrelin enhances appetite and increases food intake in humans.
      Subcutaneous ghrelin administration also stimulates appetite and food intake in obese and lean humans.
      • Druce MR
      • Neary NM
      • Small CJ
      • et al.
      Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers.
      • Druce MR
      • Wren AM
      • Park AJ
      • et al.
      Ghrelin increases food intake in obese as well as lean subjects.
      Postprandial suppression of serum ghrelin is less robust in obese individuals, possibly contributing to the pathogenesis of obesity.
      • Cummings DE
      • Purnell JQ
      • Frayo RS
      • Schmidova K
      • Wisse BE
      • Weigle DS
      A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans.
      • Cummings DE
      • Weigle DS
      • Frayo RS
      • et al.
      Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery.
      • Cummings DE
      • Shannon MH
      Ghrelin and gastric bypass: is there a hormonal contribution to surgical weight loss?.
      • English PJ
      • Ghatei MA
      • Malik IA
      • Bloom SR
      • Wilding JP
      Food fails to suppress ghrelin levels in obese humans.
      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.
      • Cummings DE
      • Weigle DS
      • Frayo RS
      • et al.
      Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery.
      • Tschop M
      • Weyer C
      • Tataranni PA
      • Devanarayan V
      • Ravussin E
      • Heiman ML
      Circulating ghrelin levels are decreased in human obesity.
      • Shiiya T
      • Nakazato M
      • Mizuta M
      • et al.
      Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion.
      • Cummings DE
      • Shannon MH
      Ghrelin and gastric bypass: is there a hormonal contribution to surgical weight loss?.
      • Ariyasu H
      • Takaya K
      • Tagami T
      • et al.
      Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans.
      • Foster-Schubert KE
      • McTiernan A
      • Frayo RS
      • et al.
      Human plasma ghrelin levels increase during a one-year exercise program.
      • Nagaya N
      • Uematsu M
      • Kojima M
      • et al.
      Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors.
      • Otto B
      • Cuntz U
      • Fruehauf E
      • et al.
      Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa.
      • Otto B
      • Tschop M
      • Cuntz U
      Similar fasting ghrelin levels in binge eating/purging anorexia nervosa and restrictive anorexia nervosa [letter].
      • Otto B
      • Tschop M
      • Fruhauf E
      • et al.
      Postprandial ghrelin release in anorectic patients before and after weight gain.
      • Otto B
      • Tschop M
      • Heldwein W
      • Pfeiffer AF
      • Diederich S
      Endogenous and exogenous glucocorticoids decrease plasma ghrelin in humans.
      Weight gain induced by high-fat diet, therapy for anorexia nervosa, or glucocorticoid administration leads to decreased systemic ghrelin levels.
      • Otto B
      • Cuntz U
      • Fruehauf E
      • et al.
      Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa.
      • Otto B
      • Tschop M
      • Heldwein W
      • Pfeiffer AF
      • Diederich S
      Endogenous and exogenous glucocorticoids decrease plasma ghrelin in humans.
      • Robertson MD
      • Henderson RA
      • Vist GE
      • Rumsey RD
      Plasma ghrelin response following a period of acute overfeeding in normal weight men.
      Long-term ghrelin administration leads to weight gain in experimental animals by stimulating food intake, decreasing energy expenditure and spontaneous activity, and promoting adipogenesis.
      • van der Lely AJ
      • Tschop M
      • Heiman ML
      • Ghigo E
      Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin.
      • Nakazato M
      • Murakami N
      • Date Y
      • et al.
      A role for ghrelin in the central regulation of feeding.
      • Tschop M
      • Smiley DL
      • Heiman ML
      Ghrelin induces adiposity in rodents.
      • Wren AM
      • Small CJ
      • Abbott CR
      • et al.
      Ghrelin causes hyperphagia and obesity in rats.
      • Choi K
      • Roh SG
      • Hong YH
      • et al.
      The role of ghrelin and growth hormone secretagogues receptor on rat adipogenesis.
      • Tang-Christensen M
      • Vrang N
      • Ortmann S
      • Bidlingmaier M
      • Horvath TL
      • Tschop M
      Central administration of ghrelin and agouti-related protein (83-132) increases food intake and decreases spontaneous locomotor activity in rats.
      In contrast, obestatin administration attenuates weight gain in experimental animals and opposes ghrelin effects.
      • Zhang JV
      • Ren PG
      • Avsian-Kretchmer O
      • et al.
      Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake.
      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.
      • Sun Y
      • Wang P
      • Zheng H
      • Smith RG
      Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor.
      • Sun Y
      • Ahmed S
      • Smith RG
      Deletion of ghrelin impairs neither growth nor appetite.
      • Wortley KE
      • Anderson KD
      • Garcia K
      • et al.
      Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference.
      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.
      • Ukkola O
      • Ravussin E
      • Jacobson P
      • et al.
      Role of ghrelin polymorphisms in obesity based on three different studies.
      • Korbonits M
      • Gueorguiev M
      • O'Grady E
      • et al.
      A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children.
      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.
      • Cummings DE
      • Clement K
      • Purnell JQ
      • et al.
      Elevated plasma ghrelin levels in Prader Willi syndrome.
      • Butler MG
      • Bittel DC
      • Talebizadeh Z
      Plasma peptide YY and ghrelin levels in infants and children with Prader-Willi syndrome.
      • Choe YH
      • Song SY
      • Paik KH
      • et al.
      Increased density of ghrelin-expressing cells in the gastric fundus and body in Prader-Willi syndrome.
      • DelParigi A
      • Tschop M
      • Heiman ML
      • et al.
      High circulating ghrelin: a potential cause for hyperphagia and obesity in Prader-Willi syndrome.
      • Goldstone AP
      • Thomas EL
      • Brynes AE
      • et al.
      Elevated fasting plasma ghrelin in Prader-Willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance.
      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.
      • Tsolakis AV
      • Portela-Gomes GM
      • Stridsberg M
      • et al.
      Malignant gastric ghrelinoma with hyperghrelinemia.
      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.
      • Cummings DE
      • Weigle DS
      • Frayo RS
      • et al.
      Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery.
      This observation has been confirmed in most, but not all, subsequent studies of gastric bypass patients.
      • Cummings DE
      • Shannon MH
      Ghrelin and gastric bypass: is there a hormonal contribution to surgical weight loss?.
      • Christou NV
      • Look D
      • McLean AP
      Pre- and post-prandial plasma ghrelin levels do not correlate with satiety or failure to achieve a successful outcome after Roux-en-Y gastric bypass.
      • Flier JS
      • Maratos-Flier E
      The stomach speaks—ghrelin and weight regulation.
      • Fruhbeck G
      • Rotellar F
      • Hernandez-Lizoain JL
      • et al.
      Fasting plasma ghrelin concentrations 6 months after gastric bypass are not determined by weight loss or changes in insulinemia.
      • Geloneze B
      • Tambascia MA
      • Pilla VF
      • Geloneze SR
      • Repetto EM
      • Pareja JC
      Ghrelin: a gut-brain hormone: effect of gastric bypass surgery.
      • Holdstock C
      • Engstrom BE
      • Ohrvall M
      • Lind L
      • Sundbom M
      • Karlsson FA
      Ghrelin and adipose tissue regulatory peptides: effect of gastric bypass surgery in obese humans.
      • Holdstock C
      • Engstrom BE
      • Ohrvall M
      • Lind L
      • Sundbom M
      • Karlsson FA
      Effect of bariatric surgery on adipose tissue regulatory peptides and growth hormone secretion.
      • Leonetti F
      • Silecchia G
      • Iacobellis G
      • et al.
      Different plasma ghrelin levels after laparoscopic gastric bypass and adjustable gastric banding in morbid obese subjects.
      • Lin E
      • Gletsu N
      • Fugate K
      • et al.
      The effects of gastric surgery on systemic ghrelin levels in the morbidly obese.
      • Morinigo R
      • Casamitjana R
      • Moize V
      • et al.
      Short-term effects of gastric bypass surgery on circulating ghrelin levels.
      • Stoeckli R
      • Chanda R
      • Langer I
      • Keller U
      Changes of body weight and plasma ghrelin levels after gastric banding and gastric bypass.
      • Tritos NA
      • Mun E
      • Bertkau A
      • Grayson R
      • Maratos-Flier E
      • Goldfine A
      Serum ghrelin levels in response to glucose load in obese subjects post-gastric bypass surgery.
      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.
      • Nakazato M
      • Murakami N
      • Date Y
      • et al.
      A role for ghrelin in the central regulation of feeding.
      • Tschop M
      • Smiley DL
      • Heiman ML
      Ghrelin induces adiposity in rodents.
      • Wren AM
      • Small CJ
      • Abbott CR
      • et al.
      Ghrelin causes hyperphagia and obesity in rats.
      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.
      • Nakazato M
      • Murakami N
      • Date Y
      • et al.
      A role for ghrelin in the central regulation of feeding.
      • Kamegai J
      • Tamura H
      • Shimizu T
      • Ishii S
      • Sugihara H
      • Wakabayashi I
      Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats.
      The expression of appetite-stimulating peptides neuropeptide Y (NPY) and agouti-related protein (AgRP) is increased by ghrelin in the arcuate hypothalamic nucleus.
      • Kamegai J
      • Tamura H
      • Shimizu T
      • Ishii S
      • Sugihara H
      • Wakabayashi I
      Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats.
      • Shintani M
      • Ogawa Y
      • Ebihara K
      • et al.
      Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway.
      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.
      • Chen HY
      • Trumbauer ME
      • Chen AS
      • et al.
      Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein.
      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.
      • Cowley MA
      • Smith RG
      • Diano S
      • et al.
      The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis.
      • Lu S
      • Guan JL
      • Wang QP
      • et al.
      Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus.
      Both human and animal studies suggest that the appetite-stimulating effects of ghrelin are inhibited by vagotomy, indicating that ghrelin may also have direct effects on vagal afferent activity.
      • Date Y
      • Murakami N
      • Toshinai K
      • et al.
      The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats.
      • le Roux CW
      • Neary NM
      • Halsey TJ
      • et al.
      Ghrelin does not stimulate food intake in patients with surgical procedures involving vagotomy.

      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.
      • Masuda Y
      • Tanaka T
      • Inomata N
      • et al.
      Ghrelin stimulates gastric acid secretion and motility in rats.
      • Asakawa A
      • Inui A
      • Kaga T
      • et al.
      Antagonism of ghrelin receptor reduces food intake and body weight gain in mice.
      • Fujino K
      • Inui A
      • Asakawa A
      • Kihara N
      • Fujimura M
      • Fujimiya M
      Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats.
      • Inui A
      • Asakawa A
      • Bowers CY
      • et al.
      Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ.
      • Trudel L
      • Bouin M
      • Tomasetto C
      • et al.
      Two new peptides to improve post-operative gastric ileus in dog.
      • Trudel L
      • Tomasetto C
      • Rio MC
      • et al.
      Ghrelin/motilin-related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat.
      Preliminary data suggest that obestatin decreases both stomach emptying and jejunum contractility.
      • Zhang JV
      • Ren PG
      • Avsian-Kretchmer O
      • et al.
      Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake.

      Regulation of Glucose Homeostasis

      Available data suggest a negative association between systemic ghrelin and insulin levels.
      • Cummings DE
      • Purnell JQ
      • Frayo RS
      • Schmidova K
      • Wisse BE
      • Weigle DS
      A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans.
      • Tschop M
      • Weyer C
      • Tataranni PA
      • Devanarayan V
      • Ravussin E
      • Heiman ML
      Circulating ghrelin levels are decreased in human obesity.
      Ghrelin inhibits insulin secretion both in vitro and in most human or animal studies.
      • Broglio F
      • Arvat E
      • Benso A
      • et al.
      Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans.
      • Reimer MK
      • Pacini G
      • Ahren B
      Dose-dependent inhibition by ghrelin of insulin secretion in the mouse.
      • Arosio M
      • Ronchi CL
      • Gebbia C
      • Cappiello V
      • Beck-Peccoz P
      • Peracchi M
      Stimulatory effects of ghrelin on circulating somatostatin and pancreatic polypeptide levels.
      • Broglio F
      • Gottero C
      • Benso A
      • et al.
      Effects of ghrelin on the insulin and glycemic responses to glucose, arginine, or free fatty acids load in humans.
      • Egido EM
      • Rodriguez-Gallardo J
      • Silvestre RA
      • Marco J
      Inhibitory effect of ghrelin on insulin and pancreatic somatostatin secretion.
      However, other studies have suggested that ghrelin may stimulate insulin secretion in certain paradigms.
      • Date Y
      • Nakazato M
      • Hashiguchi S
      • et al.
      Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion.
      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.
      • Murata M
      • Okimura Y
      • Iida K
      • et al.
      Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells.
      Ghrelin may also inhibit secretion of the insulin-sensitizing protein adiponectin from adipocytes and stimulate secretion of the counter-regulatory hormones, including GH, cortisol, epinephrine, and (possibly) glucagon.
      • Takaya K
      • Ariyasu H
      • Kanamoto N
      • et al.
      Ghrelin strongly stimulates growth hormone release in humans.
      • Ott V
      • Fasshauer M
      • Dalski A
      • et al.
      Direct peripheral effects of ghrelin include suppression of adiponectin expression.
      • Salehi A
      • Dornonville de la Cour C
      • Hakanson R
      • Lundquist I
      Effects of ghrelin on insulin and glucagon secretion: a study of isolated pancreatic islets and intact mice.
      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.
      • Tritos NA
      • Kissinger KV
      • Manning WJ
      • Danias PG
      Association between ghrelin and cardiovascular indexes in healthy obese and lean men.
      In addition, ghrelin infusion has acute hemodynamic effects in healthy human volunteers, increasing cardiac index and stroke volume and decreasing blood pressure.
      • Nagaya N
      • Kojima M
      • Uematsu M
      • et al.
      Hemodynamic and hormonal effects of human ghrelin in healthy volunteers.
      In an animal model of congestive heart failure, long-term ghrelin administration led to beneficial hemodynamic effects, increasing cardiac output, preventing left ventricular remodeling, and decreasing blood pressure.
      • Nagaya N
      • Uematsu M
      • Kojima M
      • et al.
      Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure.
      Salutary hemodynamic effects were also observed in patients with congestive heart failure who were administered short-term ghrelin infusions.
      • Nagaya N
      • Miyatake K
      • Uematsu M
      • et al.
      Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure.
      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.
      • Li WG
      • Gavrila D
      • Liu X
      • et al.
      Ghrelin inhibits proinflammatory responses and nuclear factor-kappaB activation in human endothelial cells.
      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 secretion of proinflammatory cytokines from immune cells.
      • Koo GC
      • Huang C
      • Camacho R
      • et al.
      Immune enhancing effect of a growth hormone secretagogue.
      • Dixit VD
      • Schaffer EM
      • Pyle RS
      • et al.
      Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells.
      • Dixit VD
      • Taub DD
      Ghrelin and immunity: a young player in an old field.
      In contrast, a recent study
      • Zhao D
      • Zhan Y
      • Zeng H
      • Moyer MP
      • Mantzoros CS
      • Pothoulakis C
      Ghrelin stimulates interleukin-8 gene expression through protein kinase C-mediated NF-κB pathway in human colonic epithelial cells.
      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.
      • Zhao D
      • Zhan Y
      • Zeng H
      • Moyer MP
      • Mantzoros CS
      • Pothoulakis C
      Ghrelin stimulates interleukin-8 gene expression through protein kinase C-mediated NF-κB pathway in human colonic epithelial cells.
      Thus, ghrelin may have tissue-specific effects that can be either anti-inflammatory or proinflammatory.
      Several other effects have been attributed to ghrelin. Ghrelin may directly influence osteoblast growth.
      • Fukushima N
      • Hanada R
      • Teranishi H
      • et al.
      Ghrelin directly regulates bone formation.
      Indices of systemic ghrelin secretion show a correlation with bone mineral density in healthy adolescents.
      • Misra M
      • Miller KK
      • Stewart V
      • et al.
      Ghrelin and bone metabolism in adolescent girls with anorexia nervosa and healthy adolescents.
      Furthermore, decreased systemic ghrelin secretion may lead to osteopenia after gastrectomy.
      • Dornonville de la Cour C
      • Lindqvist A
      • Egecioglu E
      • et al.
      Ghrelin treatment reverses the reduction in weight gain and body fat in gastrectomised mice.
      • Lehto-Axtelius D
      • Chen D
      • Surve VV
      • Hakanson R
      Post-gastrectomy osteopenia in the rat: bone structure is preserved by retaining 10%-30% of the oxyntic gland area.
      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.
      • Baldanzi G
      • Filigheddu N
      • Cutrupi S
      • et al.
      Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT.
      • van der Lely AJ
      • Tschop M
      • Heiman ML
      • Ghigo E
      Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin.
      • Thompson NM
      • Gill DA
      • Davies R
      • et al.
      Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor.
      • Muccioli G
      • Pons N
      • Ghe C
      • Catapano F
      • Granata R
      • Ghigo E
      Ghrelin and des-acyl ghrelin both inhibit isoproterenol-induced lipolysis in rat adipocytes via a non-type 1a growth hormone secretagogue receptor.
      • Bedendi I
      • Alloatti G
      • Marcantoni A
      • et al.
      Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin.
      Because nonacylated ghrelin does not engage the GHS receptor, a currently unidentified receptor may exist that mediates nonacylated ghrelin effects.
      • Baldanzi G
      • Filigheddu N
      • Cutrupi S
      • et al.
      Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT.
      • van der Lely AJ
      • Tschop M
      • Heiman ML
      • Ghigo E
      Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin.

      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.
      • Baldelli R
      • Otero XL
      • Camina JP
      • et al.
      Growth hormone secretagogues as diagnostic tools in disease states.
      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).
      TABLE 2Clinical Conditions in Which Ghrelin Agonists or Antagonists May Have Therapeutic Potential
      Conditions in which ghrelin agonists may serve as useful diagnostic agents are indicated. CHF = congestive heart failure; HIV = human immunodeficiency virus.
      Ghrelin agonistsGhrelin antagonists
      • 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
      • 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.
      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).
      • Nagaya N
      • Itoh T
      • Murakami S
      • et al.
      Treatment of cachexia with ghrelin in patients with COPD.
      Ghrelin may increase gastrointestinal motility in gastroparesis.
      • Murray CD
      • Martin NM
      • Patterson M
      • et al.
      Ghrelin enhances gastric emptying in diabetic gastroparesis: a double-blind, placebo controlled, cross-over study.
      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 ghrelinin 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.

      REFERENCES

        • Kojima M
        • Hosoda H
        • Date Y
        • Nakazato M
        • Matsuo H
        • Kangawa K
        Ghrelin is a growth-hormone-releasing acylated peptide from stomach.
        Nature. 1999; 402: 656-660
        • Kojima M
        • Hosoda H
        • Kangawa K
        Clinical endocrinology and metabolism: ghrelin, a novel growth-hormone-releasing and appetite-stimulating peptide from stomach.
        Best Pract Res Clin Endocrinol Metab. 2004; 18: 517-530
        • Kojima M
        • Hosoda H
        • Matsuo H
        • Kangawa K
        Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor.
        Trends Endocrinol Metab. 2001; 12: 118-122
        • Bowers CY
        • Momany F
        • Reynolds GA
        • Chang D
        • Hong A
        • Chang K
        Structure-activity relationships of a synthetic pentapeptide that specifically releases growth hormone in vitro.
        Endocrinology. 1980; 106: 663-667
        • Bowers CY
        • Momany FA
        • Reynolds GA
        • Hong A
        On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone.
        Endocrinology. 1984; 114: 1537-1545
        • Smith RG
        • Cheng K
        • Schoen WR
        • et al.
        A nonpeptidyl growth hormone secretagogue.
        Science. 1993; 260: 1640-1643
        • Cheng K
        • Chan WW
        • Butler B
        • et al.
        Stimulation of growth hormone release from rat primary pituitary cells by L-692,429, a novel non-peptidyl GH secretagogue.
        Endocrinology. 1993; 132: 2729-2731
        • Howard AD
        • Feighner SD
        • Cully DF
        • et al.
        A receptor in pituitary and hypothalamus that functions in growth hormone release.
        Science. 1996; 273: 974-977
        • Zhang JV
        • Ren PG
        • Avsian-Kretchmer O
        • et al.
        Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake.
        Science. 2005; 310: 996-999
        • McKee KK
        • Tan CP
        • Palyha OC
        • et al.
        Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors.
        Genomics. 1997; 46: 426-434
        • Matsumoto M
        • Hosoda H
        • Kitajima Y
        • et al.
        Structure-activity relationship of ghrelin: pharmacological study of ghrelin peptides.
        Biochem Biophys Res Commun. 2001; 287: 142-146
        • Bednarek MA
        • Feighner SD
        • Pong SS
        • et al.
        Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a.
        J Med Chem. 2000; 43: 4370-4376
        • Akamizu T
        • Shinomiya T
        • Irako T
        • et al.
        Separate measurement of plasma levels of acylated and desacyl ghrelin in healthy subjects using a new direct ELISA assay.
        J Clin Endocrinol Metab. 2005; 90: 6-9
        • Hosoda H
        • Kojima M
        • Matsuo H
        • Kangawa K
        Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue.
        Biochem Biophys Res Commun. 2000; 279: 909-913
        • Date Y
        • Kojima M
        • Hosoda H
        • et al.
        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. 2000; 141: 4255-4261
        • Kojima M
        • Kangawa K
        Ghrelin: structure and function.
        Physiol Rev. 2005; 85: 495-522
        • Folwaczny C
        • Chang JK
        • Tschop M
        Ghrelin and motilin: two sides of one coin?.
        Eur J Endocrinol. 2001; 144: R1-R3
        • Kanamoto N
        • Akamizu T
        • Tagami T
        • et al.
        Genomic structure and characterization of the 5′-flanking region of the human ghrelin gene.
        Endocrinology. 2004; 145: 4144-4153
        • Hosoda H
        • Kojima M
        • Mizushima T
        • Shimizu S
        • Kangawa K
        Structural divergence of human ghrelin: identification of multiple ghrelin-derived molecules produced by post-translational processing.
        J Biol Chem. 2003; 278: 64-70
        • Prado CL
        • Pugh-Bernard AE
        • Elghazi L
        • Sosa-Pineda B
        • Sussel L
        Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development.
        Proc Natl Acad Sci U S A. 2004; 101: 2924-2929
        • Wierup N
        • Yang S
        • McEvilly RJ
        • Mulder H
        • Sundler F
        Ghrelin is expressed in a novel endocrine cell type in developing rat islets and inhibits insulin secretion from INS-1 (832/13) cells.
        J Histochem Cytochem. 2004; 52: 301-310
        • Fukushima N
        • Hanada R
        • Teranishi H
        • et al.
        Ghrelin directly regulates bone formation.
        J Bone Miner Res. 2005; 20: 790-798
        • Cowley MA
        • Smith RG
        • Diano S
        • et al.
        The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis.
        Neuron. 2003; 37: 649-661
        • Lu S
        • Guan JL
        • Wang QP
        • et al.
        Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus.
        Neurosci Lett. 2002; 321: 157-160
        • Gnanapavan S
        • Kola B
        • Bustin SA
        • et al.
        The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans.
        J Clin Endocrinol Metab. 2002; 87: 2988
        • Mozid AM
        • Tringali G
        • Forsling ML
        • et al.
        Ghrelin is released from rat hypothalamic explants and stimulates corticotrophin-releasing hormone and arginine-vasopressin.
        Horm Metab Res. 2003; 35: 455-459
        • Barreiro ML
        • Gaytan F
        • Caminos JE
        • et al.
        Cellular location and hormonal regulation of ghrelin expression in rat testis.
        Biol Reprod. 2002; 67: 1768-1776
        • Tena-Sempere M
        • Barreiro ML
        • Gonzalez LC
        • et al.
        Novel expression and functional role of ghrelin in rat testis.
        Endocrinology. 2002; 143: 717-725
        • Gualillo O
        • Caminos J
        • Blanco M
        • et al.
        Ghrelin, a novel placental-derived hormone.
        Endocrinology. 2001; 142: 788-794
        • Tritos NA
        • Kokkinos A
        • Lampadariou E
        • Alexiou E
        • Katsilambros N
        • Maratos-Flier E
        Cerebrospinal fluid ghrelin is negatively associated with body mass index.
        J Clin Endocrinol Metab. 2003; 88: 2943-2946
        • Tschop M
        • Wawarta R
        • Riepl RL
        • et al.
        Post-prandial decrease of circulating human ghrelin levels.
        J Endocrinol Invest. 2001; 24: RC19-RC21
        • Overduin J
        • Frayo RS
        • Grill HJ
        • Kaplan JM
        • Cummings DE
        Role of the duodenum and macronutrient type in ghrelin regulation.
        Endocrinology. 2005; 146: 845-850
        • Cummings DE
        • Purnell JQ
        • Frayo RS
        • Schmidova K
        • Wisse BE
        • Weigle DS
        A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans.
        Diabetes. 2001; 50: 1714-1719
        • Cummings DE
        • Weigle DS
        • Frayo RS
        • et al.
        Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery.
        N Engl J Med. 2002; 346: 1623-1630
        • Weigle DS
        • Cummings DE
        • Newby PD
        • et al.
        Roles of leptin and ghrelin in the loss of body weight caused by a low fat, high carbohydrate diet.
        J Clin Endocrinol Metab. 2003; 88: 1577-1586
        • Blom WA
        • Lluch A
        • Vinoy S
        • et al.
        Effects of gastric emptying on the postprandial ghrelin response.
        Am J Physiol Endocrinol Metab. 2006; 290: E389-E395
        • Tschop M
        • Weyer C
        • Tataranni PA
        • Devanarayan V
        • Ravussin E
        • Heiman ML
        Circulating ghrelin levels are decreased in human obesity.
        Diabetes. 2001; 50: 707-709
        • Cummings DE
        • Shannon MH
        Roles for ghrelin in the regulation of appetite and body weight.
        Arch Surg. 2003; 138: 389-396
        • Shiiya T
        • Nakazato M
        • Mizuta M
        • et al.
        Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion.
        J Clin Endocrinol Metab. 2002; 87: 240-244
        • Broglio F
        • Gottero C
        • Van Koetsveld P
        • et al.
        Acetylcholine regulates ghrelin secretion in humans.
        J Clin Endocrinol Metab. 2004; 89: 2429-2433
        • Koutkia P
        • Canavan B
        • Breu J
        • Johnson ML
        • Grinspoon SK
        Nocturnal ghrelin pulsatility and response to growth hormone secretagogues in healthy men.
        Am J Physiol Endocrinol Metab. 2004; 287: E506-E512
        • Grinspoon S
        • Miller KK
        • Herzog DB
        • Grieco KA
        • Klibanski A
        Effects of estrogen and recombinant human insulin-like growth factor-I on ghrelin secretion in severe undernutrition.
        J Clin Endocrinol Metab. 2004; 89: 3988-3993
        • Anderwald C
        • Brabant G
        • Bernroider E
        • et al.
        Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients.
        Diabetes. 2003; 52: 1792-1798
        • Mohlig M
        • Spranger J
        • Otto B
        • Ristow M
        • Tschop M
        • Pfeiffer AF
        Euglycemic hyperinsulinemia, but not lipid infusion, decreases circulating ghrelin levels in humans.
        J Endocrinol Invest. 2002; 25: RC36-RC38
        • Arafat MA
        • Otto B
        • Rochlitz H
        • et al.
        Glucagon inhibits ghrelin secretion in humans.
        Eur J Endocrinol. 2005; 153: 397-402
        • Qi X
        • Reed J
        • Englander EW
        • Chandrashekar V
        • Bartke A
        • Greeley Jr, GH
        Evidence that growth hormone exerts a feedback effect on stomach ghrelin production and secretion.
        Exp Biol Med (Maywood). 2003; 228: 1028-1032
        • Norrelund H
        • Hansen TK
        • Orskov H
        • et al.
        Ghrelin immunoreactivity in human plasma is suppressed by somatostatin.
        Clin Endocrinol (Oxf). 2002; 57: 539-546
        • Barkan AL
        • Dimaraki EV
        • Jessup SK
        • Symons KV
        • Ermolenko M
        • Jaffe CA
        Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels.
        J Clin Endocrinol Metab. 2003; 88: 2180-2184
        • Broglio F
        • van Koetsveld P
        • Benso A
        • et al.
        Ghrelin secretion is inhibited by either somatostatin or cortistatin in humans.
        J Clin Endocrinol Metab. 2002; 87: 4829-4832
        • Koutkia P
        • Schurgin S
        • Berry J
        • et al.
        Reciprocal changes in endogenous ghrelin and growth hormone during fasting in healthy women.
        Am J Physiol Endocrinol Metab. 2005; 289: E814-E822
        • Misra M
        • Miller KK
        • Herzog DB
        • et al.
        Growth hormone and ghrelin responses to an oral glucose load in adolescent girls with anorexia nervosa and controls.
        J Clin Endocrinol Metab. 2004; 89: 1605-1612
        • Misra M
        • Miller KK
        • Kuo K
        • et al.
        Secretory dynamics of ghrelin in adolescent girls with anorexia nervosa and healthy adolescents.
        Am J Physiol Endocrinol Metab. 2005; 289: E347-E356
        • Cohen MA
        • Ellis SM
        • Le Roux CW
        • et al.
        Oxyntomodulin suppresses appetite and reduces food intake in humans.
        J Clin Endocrinol Metab. 2003; 88: 4696-4701
        • Davis ME
        • Pemberton CJ
        • Yandle TG
        • et al.
        Urocortin-1 infusion in normal humans.
        J Clin Endocrinol Metab. 2004; 89: 1402-1409
        • Batterham RL
        • Cohen MA
        • Ellis SM
        • et al.
        Inhibition of food intake in obese subjects by peptide YY3-36.
        N Engl J Med. 2003; 349: 941-948
        • Chan JL
        • Bullen J
        • Lee JH
        • Yiannakouris N
        • Mantzoros CS
        Ghrelin levels are not regulated by recombinant leptin administration and/or three days of fasting in healthy subjects.
        J Clin Endocrinol Metab. 2004; 89: 335-343
        • Riis AL
        • Hansen TK
        • Moller N
        • Weeke J
        • Jorgensen JO
        Hyperthyroidism is associated with suppressed circulating ghrelin levels.
        J Clin Endocrinol Metab. 2003; 88: 853-857
        • Rojdmark S
        • Calissendorff J
        • Danielsson O
        • Brismar K
        Hunger-satiety signals in patients with Graves' thyrotoxicosis before, during, and after long-term pharmacological treatment.
        Endocrine. 2005; 27: 55-61
        • Pagotto U
        • Gambineri A
        • Pelusi C
        • et al.
        Testosterone replacement therapy restores normal ghrelin in hypogonadal men.
        J Clin Endocrinol Metab. 2003; 88: 4139-4143
        • Pagotto U
        • Gambineri A
        • Vicennati V
        • Heiman ML
        • Tschop M
        • Pasquali R
        Plasma ghrelin, obesity, and the polycystic ovary syndrome: correlation with insulin resistance and androgen levels.
        J Clin Endocrinol Metab. 2002; 87: 5625-5629
        • Cummings DE
        Helicobacter pylori and ghrelin: interrelated players in body-weight regulation?.
        Am J Med. 2004; 117: 436-439
        • Isomoto H
        • Ueno H
        • Saenko VA
        • et al.
        Impact of Helicobacter pylori infection on gastric and plasma ghrelin dynamics in humans.
        Am J Gastroenterol. 2005; 100: 1711-1720
        • Takachi K
        • Doki Y
        • Ishikawa O
        • et al.
        Postoperative ghrelin levels and delayed recovery from body weight loss after distal or total gastrectomy.
        J Surg Res. 2006; 130: 1-7
        • Murdolo G
        • Lucidi P
        • Di Loreto C
        • et al.
        Insulin is required for prandial ghrelin suppression in humans.
        Diabetes. 2003; 52: 2923-2927
        • Gelling RW
        • Overduin J
        • Morrison CD
        • et al.
        Effect of uncontrolled diabetes on plasma ghrelin concentrations and ghrelin-induced feeding.
        Endocrinology. 2004; 145: 4575-4582
        • Spranger J
        • Ristow M
        • Otto B
        • et al.
        Post-prandial decrease of human plasma ghrelin in the absence of insulin.
        J Endocrinol Invest. 2003; 26: RC19-RC22
        • Sun Y
        • Wang P
        • Zheng H
        • Smith RG
        Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor.
        Proc Natl Acad Sci U S A. 2004; 101: 4679-4684
        • Smith RG
        • Leonard R
        • Bailey AR
        • et al.
        Growth hormone secretagogue receptor family members and ligands.
        Endocrine. 2001; 14: 9-14
        • Feighner SD
        • Tan CP
        • McKee KK
        • et al.
        Receptor for motilin identified in the human gastrointestinal system.
        Science. 1999; 284: 2184-2188
        • Guan XM
        • Yu H
        • Palyha OC
        • et al.
        Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues.
        Brain Res Mol Brain Res. 1997; 48: 23-29
        • Hattori N
        • Saito T
        • Yagyu T
        • Jiang BH
        • Kitagawa K
        • Inagaki C
        GH, GH receptor, GH secretagogue receptor, and ghrelin expression in human T cells, B cells, and neutrophils.
        J Clin Endocrinol Metab. 2001; 86: 4284-4291
        • Kohno D
        • Gao HZ
        • Muroya S
        • Kikuyama S
        • Yada T
        Ghrelin directly interacts with neuropeptide-Y-containing neurons in the rat arcuate nucleus: Ca2+ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin.
        Diabetes. 2003; 52: 948-956
        • Holst B
        • Cygankiewicz A
        • Jensen TH
        • Ankersen M
        • Schwartz TW
        High constitutive signaling of the ghrelin receptor—identification of a potent inverse agonist.
        Mol Endocrinol. 2003; 17: 2201-2210
        • Holst B
        • Schwartz TW
        Constitutive ghrelin receptor activity as a signaling set-point in appetite regulation.
        Trends Pharmacol Sci. 2004; 25: 113-117
        • Tullin S
        • Hansen BS
        • Ankersen M
        • Moller J
        • Von Cappelen KA
        • Thim L
        Adenosine is an agonist of the growth hormone secretagogue receptor.
        Endocrinology. 2000; 141: 3397-3402
        • Carreira MC
        • Camina JP
        • Smith RG
        • Casanueva FF
        Agonist-specific coupling of growth hormone secretagogue receptor type 1a to different intracellular signaling systems: role of adenosine.
        NeuroEndocrinology. 2004; 79: 13-25
        • Smith RG
        • Griffin PR
        • Xu Y
        • et al.
        Adenosine: a partial agonist of the growth hormone secretagogue receptor.
        Biochem Biophys Res Commun. 2000; 276: 1306-1313
        • Baldanzi G
        • Filigheddu N
        • Cutrupi S
        • et al.
        Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT.
        J Cell Biol. 2002; 159: 1029-1037
        • van der Lely AJ
        • Tschop M
        • Heiman ML
        • Ghigo E
        Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin.
        Endocr Rev. 2004; 25: 426-457
        • Zhang W
        • Zhao L
        • Lin TR
        • et al.
        Inhibition of adipogenesis by ghrelin.
        Mol Biol Cell. 2004; 15: 2484-2491
        • Halem HA
        • Taylor JE
        • Dong JZ
        • et al.
        Novel analogs of ghrelin: physiological and clinical implications.
        Eur J Endocrinol. 2004; 151: S71-S75
        • Hataya Y
        • Akamizu T
        • Takaya K
        • et al.
        A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans.
        J Clin Endocrinol Metab. 2001; 86: 4552
        • Arvat E
        • Di Vito L
        • Broglio F
        • et al.
        Preliminary evidence that Ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans.
        J Endocrinol Invest. 2000; 23: 493-495
        • Arvat E
        • Maccario M
        • Di Vito L
        • et al.
        Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone.
        J Clin Endocrinol Metab. 2001; 86: 1169-1174
        • Date Y
        • Murakami N
        • Kojima M
        • et al.
        Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats.
        Biochem Biophys Res Commun. 2000; 275: 477-480
        • Peino R
        • Baldelli R
        • Rodriguez-Garcia J
        • et al.
        Ghrelin-induced growth hormone secretion in humans.
        Eur J Endocrinol. 2000; 143: R11-R14
        • Takaya K
        • Ariyasu H
        • Kanamoto N
        • et al.
        Ghrelin strongly stimulates growth hormone release in humans.
        J Clin Endocrinol Metab. 2000; 85: 4908-4911
        • Popovic V
        • Miljic D
        • Micic D
        • et al.
        Ghrelin main action on the regulation of growth hormone release is exerted at hypothalamic level.
        J Clin Endocrinol Metab. 2003; 88: 3450-3453
        • Date Y
        • Murakami N
        • Toshinai K
        • et al.
        The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats.
        Gastroenterology. 2002; 123: 1120-1128
        • Sun Y
        • Ahmed S
        • Smith RG
        Deletion of ghrelin impairs neither growth nor appetite.
        Mol Cell Biol. 2003; 23: 7973-7981
        • Pantel J
        • Legendre M
        • Cabrol S
        • et al.
        Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature.
        J Clin Invest. 2006; 116: 760-768
        • Sugino T
        • Hasegawa Y
        • Kikkawa Y
        • et al.
        A transient ghrelin surge occurs just before feeding in a scheduled meal-fed sheep.
        Biochem Biophys Res Commun. 2002; 295: 255-260
        • Sugino T
        • Yamaura J
        • Yamagishi M
        • et al.
        A transient surge of ghrelin secretion before feeding is modified by different feeding regimens in sheep.
        Biochem Biophys Res Commun. 2002; 298: 785-788
        • Cummings DE
        • Frayo RS
        • Marmonier C
        • Aubert R
        • Chapelot D
        Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues.
        Am J Physiol Endocrinol Metab. 2004; 287: E297-E304
        • Nakazato M
        • Murakami N
        • Date Y
        • et al.
        A role for ghrelin in the central regulation of feeding.
        Nature. 2001; 409: 194-198
        • Tschop M
        • Smiley DL
        • Heiman ML
        Ghrelin induces adiposity in rodents.
        Nature. 2000; 407: 908-913
        • Wren AM
        • Small CJ
        • Abbott CR
        • et al.
        Ghrelin causes hyperphagia and obesity in rats.
        Diabetes. 2001; 50: 2540-2547
        • Wren AM
        • Seal LJ
        • Cohen MA
        • et al.
        Ghrelin enhances appetite and increases food intake in humans.
        J Clin Endocrinol Metab. 2001; 86: 5992
        • Druce MR
        • Neary NM
        • Small CJ
        • et al.
        Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers.
        Int J Obes (Lond). 2006; 30: 293-296
        • Druce MR
        • Wren AM
        • Park AJ
        • et al.
        Ghrelin increases food intake in obese as well as lean subjects.
        Int J Obes Relat Metab Disord. 2005; 29: 1130-1136
        • Cummings DE
        • Shannon MH
        Ghrelin and gastric bypass: is there a hormonal contribution to surgical weight loss?.
        J Clin Endocrinol Metab. 2003; 88: 2999-3002
        • English PJ
        • Ghatei MA
        • Malik IA
        • Bloom SR
        • Wilding JP
        Food fails to suppress ghrelin levels in obese humans.
        J Clin Endocrinol Metab. 2002; 87: 2984
        • Ariyasu H
        • Takaya K
        • Tagami T
        • et al.
        Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans.
        J Clin Endocrinol Metab. 2001; 86: 4753-4758
        • Foster-Schubert KE
        • McTiernan A
        • Frayo RS
        • et al.
        Human plasma ghrelin levels increase during a one-year exercise program.
        J Clin Endocrinol Metab. 2005; 90: 820-825
        • Nagaya N
        • Uematsu M
        • Kojima M
        • et al.
        Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors.
        Circulation. 2001; 104: 2034-2038
        • Otto B
        • Cuntz U
        • Fruehauf E
        • et al.
        Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa.
        Eur J Endocrinol. 2001; 145: 669-673
        • Otto B
        • Tschop M
        • Cuntz U
        Similar fasting ghrelin levels in binge eating/purging anorexia nervosa and restrictive anorexia nervosa [letter].
        Psychoneuroendocrinology. 2004; 29: 692-693
        • Otto B
        • Tschop M
        • Fruhauf E
        • et al.
        Postprandial ghrelin release in anorectic patients before and after weight gain.
        Psychoneuroendocrinology. 2005; 30: 577-581
        • Otto B
        • Tschop M
        • Heldwein W
        • Pfeiffer AF
        • Diederich S
        Endogenous and exogenous glucocorticoids decrease plasma ghrelin in humans.
        Eur J Endocrinol. 2004; 151: 113-117
        • Robertson MD
        • Henderson RA
        • Vist GE
        • Rumsey RD
        Plasma ghrelin response following a period of acute overfeeding in normal weight men.
        Int J Obes Relat Metab Disord. 2004; 28: 727-733
        • Choi K
        • Roh SG
        • Hong YH
        • et al.
        The role of ghrelin and growth hormone secretagogues receptor on rat adipogenesis.
        Endocrinology. 2003; 144: 754-759
        • Tang-Christensen M
        • Vrang N
        • Ortmann S
        • Bidlingmaier M
        • Horvath TL
        • Tschop M
        Central administration of ghrelin and agouti-related protein (83-132) increases food intake and decreases spontaneous locomotor activity in rats.
        Endocrinology. 2004; 145: 4645-4652
        • Wortley KE
        • Anderson KD
        • Garcia K
        • et al.
        Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference.
        Proc Natl Acad Sci U S A. 2004; 101: 8227-8232
        • Ukkola O
        • Ravussin E
        • Jacobson P
        • et al.
        Role of ghrelin polymorphisms in obesity based on three different studies.
        Obes Res. 2002; 10: 782-791
        • Korbonits M
        • Gueorguiev M
        • O'Grady E
        • et al.
        A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children.
        J Clin Endocrinol Metab. 2002; 87: 4005-4008
        • Cummings DE
        • Clement K
        • Purnell JQ
        • et al.
        Elevated plasma ghrelin levels in Prader Willi syndrome.
        Nat Med. 2002; 8: 643-644
        • Butler MG
        • Bittel DC
        • Talebizadeh Z
        Plasma peptide YY and ghrelin levels in infants and children with Prader-Willi syndrome.
        J Pediatr Endocrinol Metab. 2004; 17: 1177-1184
        • Choe YH
        • Song SY
        • Paik KH
        • et al.
        Increased density of ghrelin-expressing cells in the gastric fundus and body in Prader-Willi syndrome.
        J Clin Endocrinol Metab. 2005; 90: 5441-5445
        • DelParigi A
        • Tschop M
        • Heiman ML
        • et al.
        High circulating ghrelin: a potential cause for hyperphagia and obesity in Prader-Willi syndrome.
        J Clin Endocrinol Metab. 2002; 87: 5461-5464
        • Goldstone AP
        • Thomas EL
        • Brynes AE
        • et al.
        Elevated fasting plasma ghrelin in Prader-Willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance.
        J Clin Endocrinol Metab. 2004; 89: 1718-1726
        • Tsolakis AV
        • Portela-Gomes GM
        • Stridsberg M
        • et al.
        Malignant gastric ghrelinoma with hyperghrelinemia.
        J Clin Endocrinol Metab. 2004; 89: 3739-3744
        • Christou NV
        • Look D
        • McLean AP
        Pre- and post-prandial plasma ghrelin levels do not correlate with satiety or failure to achieve a successful outcome after Roux-en-Y gastric bypass.
        Obes Surg. 2005; 15: 1017-1023
        • Flier JS
        • Maratos-Flier E
        The stomach speaks—ghrelin and weight regulation.
        N Engl J Med. 2002; 346: 1662-1663
        • Fruhbeck G
        • Rotellar F
        • Hernandez-Lizoain JL
        • et al.
        Fasting plasma ghrelin concentrations 6 months after gastric bypass are not determined by weight loss or changes in insulinemia.
        Obes Surg. 2004; 14: 1208-1215
        • Geloneze B
        • Tambascia MA
        • Pilla VF
        • Geloneze SR
        • Repetto EM
        • Pareja JC
        Ghrelin: a gut-brain hormone: effect of gastric bypass surgery.
        Obes Surg. 2003; 13: 17-22
        • Holdstock C
        • Engstrom BE
        • Ohrvall M
        • Lind L
        • Sundbom M
        • Karlsson FA
        Ghrelin and adipose tissue regulatory peptides: effect of gastric bypass surgery in obese humans.
        J Clin Endocrinol Metab. 2003; 88: 3177-3183
        • Holdstock C
        • Engstrom BE
        • Ohrvall M
        • Lind L
        • Sundbom M
        • Karlsson FA
        Effect of bariatric surgery on adipose tissue regulatory peptides and growth hormone secretion.
        Asia Pac J Clin Nutr. 2004; 13: S41
        • Leonetti F
        • Silecchia G
        • Iacobellis G
        • et al.
        Different plasma ghrelin levels after laparoscopic gastric bypass and adjustable gastric banding in morbid obese subjects.
        J Clin Endocrinol Metab. 2003; 88: 4227-4231
        • Lin E
        • Gletsu N
        • Fugate K
        • et al.
        The effects of gastric surgery on systemic ghrelin levels in the morbidly obese.
        Arch Surg. 2004; 139: 780-784
        • Morinigo R
        • Casamitjana R
        • Moize V
        • et al.
        Short-term effects of gastric bypass surgery on circulating ghrelin levels.
        Obes Res. 2004; 12: 1108-1116
        • Stoeckli R
        • Chanda R
        • Langer I
        • Keller U
        Changes of body weight and plasma ghrelin levels after gastric banding and gastric bypass.
        Obes Res. 2004; 12: 346-350
        • Tritos NA
        • Mun E
        • Bertkau A
        • Grayson R
        • Maratos-Flier E
        • Goldfine A
        Serum ghrelin levels in response to glucose load in obese subjects post-gastric bypass surgery.
        Obes Res. 2003; 11: 919-924
        • Kamegai J
        • Tamura H
        • Shimizu T
        • Ishii S
        • Sugihara H
        • Wakabayashi I
        Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats.
        Diabetes. 2001; 50: 2438-2443
        • Shintani M
        • Ogawa Y
        • Ebihara K
        • et al.
        Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway.
        Diabetes. 2001; 50: 227-232
        • Chen HY
        • Trumbauer ME
        • Chen AS
        • et al.
        Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein.
        Endocrinology. 2004; 145: 2607-2612
        • le Roux CW
        • Neary NM
        • Halsey TJ
        • et al.
        Ghrelin does not stimulate food intake in patients with surgical procedures involving vagotomy.
        J Clin Endocrinol Metab. 2005; 90: 4521-4524
        • Masuda Y
        • Tanaka T
        • Inomata N
        • et al.
        Ghrelin stimulates gastric acid secretion and motility in rats.
        Biochem Biophys Res Commun. 2000; 276: 905-908
        • Asakawa A
        • Inui A
        • Kaga T
        • et al.
        Antagonism of ghrelin receptor reduces food intake and body weight gain in mice.
        Gut. 2003; 52: 947-952
        • Fujino K
        • Inui A
        • Asakawa A
        • Kihara N
        • Fujimura M
        • Fujimiya M
        Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats.
        J Physiol. 2003; 550: 227-240
        • Inui A
        • Asakawa A
        • Bowers CY
        • et al.
        Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ.
        FASEB J. 2004; 18: 439-456
        • Trudel L
        • Bouin M
        • Tomasetto C
        • et al.
        Two new peptides to improve post-operative gastric ileus in dog.
        Peptides. 2003; 24: 531-534
        • Trudel L
        • Tomasetto C
        • Rio MC
        • et al.
        Ghrelin/motilin-related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat.
        Am J Physiol Gastrointest Liver Physiol. 2002; 282: G948-G952
        • Broglio F
        • Arvat E
        • Benso A
        • et al.
        Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans.
        J Clin Endocrinol Metab. 2001; 86: 5083-5086
        • Reimer MK
        • Pacini G
        • Ahren B
        Dose-dependent inhibition by ghrelin of insulin secretion in the mouse.
        Endocrinology. 2003; 144: 916-921
        • Arosio M
        • Ronchi CL
        • Gebbia C
        • Cappiello V
        • Beck-Peccoz P
        • Peracchi M
        Stimulatory effects of ghrelin on circulating somatostatin and pancreatic polypeptide levels.
        J Clin Endocrinol Metab. 2003; 88: 701-704
        • Broglio F
        • Gottero C
        • Benso A
        • et al.
        Effects of ghrelin on the insulin and glycemic responses to glucose, arginine, or free fatty acids load in humans.
        J Clin Endocrinol Metab. 2003; 88: 4268-4272
        • Egido EM
        • Rodriguez-Gallardo J
        • Silvestre RA
        • Marco J
        Inhibitory effect of ghrelin on insulin and pancreatic somatostatin secretion.
        Eur J Endocrinol. 2002; 146: 241-244
        • Date Y
        • Nakazato M
        • Hashiguchi S
        • et al.
        Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion.
        Diabetes. 2002; 51: 124-129
        • Murata M
        • Okimura Y
        • Iida K
        • et al.
        Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells.
        J Biol Chem. 2002; 277: 5667-5674
        • Ott V
        • Fasshauer M
        • Dalski A
        • et al.
        Direct peripheral effects of ghrelin include suppression of adiponectin expression.
        Horm Metab Res. 2002; 34: 640-645
        • Salehi A
        • Dornonville de la Cour C
        • Hakanson R
        • Lundquist I
        Effects of ghrelin on insulin and glucagon secretion: a study of isolated pancreatic islets and intact mice.
        Regul Pept. 2004; 118: 143-150
        • Tritos NA
        • Kissinger KV
        • Manning WJ
        • Danias PG
        Association between ghrelin and cardiovascular indexes in healthy obese and lean men.
        Clin Endocrinol (Oxf). 2004; 60: 60-66
        • Nagaya N
        • Kojima M
        • Uematsu M
        • et al.
        Hemodynamic and hormonal effects of human ghrelin in healthy volunteers.
        Am J Physiol Regul Integr Comp Physiol. 2001; 280: R1483-R1487
        • Nagaya N
        • Uematsu M
        • Kojima M
        • et al.
        Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure.
        Circulation. 2001; 104: 1430-1435
        • Nagaya N
        • Miyatake K
        • Uematsu M
        • et al.
        Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure.
        J Clin Endocrinol Metab. 2001; 86: 5854-5859
        • Li WG
        • Gavrila D
        • Liu X
        • et al.
        Ghrelin inhibits proinflammatory responses and nuclear factor-kappaB activation in human endothelial cells.
        Circulation. 2004; 109: 2221-2226
        • Koo GC
        • Huang C
        • Camacho R
        • et al.
        Immune enhancing effect of a growth hormone secretagogue.
        J Immunol. 2001; 166: 4195-4201
        • Dixit VD
        • Schaffer EM
        • Pyle RS
        • et al.
        Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells.
        J Clin Invest. 2004; 114: 57-66
        • Dixit VD
        • Taub DD
        Ghrelin and immunity: a young player in an old field.
        Exp Gerontol. 2005; 40: 900-910
        • Zhao D
        • Zhan Y
        • Zeng H
        • Moyer MP
        • Mantzoros CS
        • Pothoulakis C
        Ghrelin stimulates interleukin-8 gene expression through protein kinase C-mediated NF-κB pathway in human colonic epithelial cells.
        J Cell Biochem. 2006; 97: 1317-1327
        • Misra M
        • Miller KK
        • Stewart V
        • et al.
        Ghrelin and bone metabolism in adolescent girls with anorexia nervosa and healthy adolescents.
        J Clin Endocrinol Metab. 2005; 90: 5082-5087
        • Dornonville de la Cour C
        • Lindqvist A
        • Egecioglu E
        • et al.
        Ghrelin treatment reverses the reduction in weight gain and body fat in gastrectomised mice.
        Gut. 2005; 54: 907-913
        • Lehto-Axtelius D
        • Chen D
        • Surve VV
        • Hakanson R
        Post-gastrectomy osteopenia in the rat: bone structure is preserved by retaining 10%-30% of the oxyntic gland area.
        Scand J Gastroenterol. 2002; 37: 437-443
        • Thompson NM
        • Gill DA
        • Davies R
        • et al.
        Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor.
        Endocrinology. 2004; 145: 234-242
        • Muccioli G
        • Pons N
        • Ghe C
        • Catapano F
        • Granata R
        • Ghigo E
        Ghrelin and des-acyl ghrelin both inhibit isoproterenol-induced lipolysis in rat adipocytes via a non-type 1a growth hormone secretagogue receptor.
        Eur J Pharmacol. 2004; 498: 27-35
        • Bedendi I
        • Alloatti G
        • Marcantoni A
        • et al.
        Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin.
        Eur J Pharmacol. 2003; 476: 87-95
        • Baldelli R
        • Otero XL
        • Camina JP
        • et al.
        Growth hormone secretagogues as diagnostic tools in disease states.
        Endocrine. 2001; 14: 95-99
        • Nagaya N
        • Itoh T
        • Murakami S
        • et al.
        Treatment of cachexia with ghrelin in patients with COPD.
        Chest. 2005; 128: 1187-1193
        • Murray CD
        • Martin NM
        • Patterson M
        • et al.
        Ghrelin enhances gastric emptying in diabetic gastroparesis: a double-blind, placebo controlled, cross-over study.
        Gut. 2005; 54: 1693-1698