Secondary Logo

Journal Logo

Review Article

Alpha-melanocyte stimulating hormone in ghrelin-elicited feeding and gut motility

Huang, Hsien-Haoa,b; Chen, Chih-Yenc,d,e,f,*

Author Information
Journal of the Chinese Medical Association: February 2019 - Volume 82 - Issue 2 - p 87-91
doi: 10.1097/JCMA.0000000000000007
  • Open



Proopiomelanocortin (POMC) is an important precursor protein in the central melanocortin system. Immuno-histochemical studies have revealed that POMC precursor is most abundant in the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the solitary tract (NTS) in the brainstem.1–3 POMC is a large molecule that is cleaved into several biologically regulatory peptides, termed melanocortins. These include α-, β-, and γ-melanocyte stimulating hormones (MSHs) and adrenocorticotropin (ACTH). These melanocortins exert their activity by binding to a family of melanocortin receptors (MCRs).4 Five receptor subtypes with specific and distinct affinities for MSH/ACTH have been cloned: MC1, MC2 (or ACTH), MC3, MC4, and MC5 receptor.5–9 The MC3, MC4, and MC5 receptors are expressed in the brain. The MC4 receptor is widely expressed throughout the brain, while the MC3 receptor is confined to the hypothalamus.

1.1. MC1 receptor

The MC1 receptor was the MCR to be cloned and expressed in melanocytes and melanoma cells4 and in a limited brain area.10 α-MSH displayed high affinity to the MC1 receptor, distinct from the other MC receptors.11,12

1.2. MC2 receptor

The MC2 receptor is abundant in the adrenal gland.8 It is not present in the hypothalamus and pituitary, based on the absence of detectable MC2 receptor mRNA.13 The MC2 receptor does not couple with MSH peptides but has high affinity with ACTH.14 Thus, MC2 receptor has been identified as the ATCH receptor8 and regulates steroid production in the adrenal gland.13

1.3. MC3 receptor

The MC3 receptor is predominantly expressed in the brain (the arcuate nucleus), placenta, gut tissue, and human heart.5,6,9,15 MC3 receptor knockout mice display metabolic syndrome evident as decreased fat/carbohydrate oxidation, reduced energy expenditure,16 and increasing adipose mass16,17 without increased food intake or weight gain.16 MTII is a potent MR agonist for both the MC3 receptor and MC4 receptor. MTII does not induce anorectic action18 and decreases food intake in MC4 receptor knockout mice19. These findings support the speculation that MC3 receptor has limited importance in mediating MTII-induced anorectic action and decreased food intake. Owing to the lack of MC3 receptor specific ligands, the role of MC3 receptor in maintaining metabolic homeostasis is still obscure and requires further investigation.

1.4. MC4 receptor

The MC4 receptor is found mainly in the central nervous system, but is also expressed throughout the brain, including the thalamus, hypothalamus, cortex, and brain stem as well as in the spinal cord.6,20 Deletion of the gene encoding MC4 receptor results in hyperphagia, increased food consumption, and profound obesity.21 MC4 receptor knockout mice do not respond to the anorectic action and reduced food intake of MTII.18,19 Mutation or deletion of the MC4 receptor is associated with obese, hyperphagic, and hyperinsulinaemic phenotypes.21–23 The MC4 receptor is expressed in the dorsal motor nucleus of the vagus within the hindbrain,20 which is the site of parasympathetic vagal efferent nerves that regulate the gastrointestinal system.24 Intracerebroventricular (ICV) injection of specific MC4 receptor antagonists (HS014, HS024, and HS028) significantly increases the food intake.12,25 These findings indicate that signaling of the MC4 receptor regulates food intake and body fat mass. MC4 receptors are up-regulated in food-limited rats but down-regulated in diet-induced obese rats.26 Subtle alterations in MC4 receptors function and density may be essential in the regulation of weight control.27

1.5. MC5 receptor

The MC5 receptor is expressed abundantly in a variety of peripheral tissues, such as skeletal muscle, lung, stomach, spleen, kidney, liver, and testis.7,28,29 The expression of MC5 receptor in the brain is inconsistent, being very low in the rat7 but abundant in the mouse.28,29 The MC5 receptor has a role in the regulation of exocrine gland function.30

1.6. α-MSH

α-MSH is the principle identified agonist in the brain.11 Immunocytochemical staining data indicate that α-MSH strongly activates the hypothalamus, thalamus, brainstem,31 the arcuate region of the hypothalamus,32 and paraventricular nuclei of hypothalamus neurons,8,32 which send axonal projections to many areas of the limbic system and brain stem.32 α-MSH can also induce a cAMP response in the cellular production of MC1, MC3, MC4, and MC5 receptors.12 The MC3 and MC4 receptors have been cloned and primarily expressed in the brain,5,6,9 which has revealed the avid affinity of α-MSH for both receptors.8,32 By acting on MC3 and MC4 receptors following ICV injection, α-MSH is very effective in suppressing food intake.25,33–38 If α-MSH is persistently delivered into the hypothalamus in rats, the suppression of food intake and decreased body weight will persist.39 α-MSH is considered as an agonist of MC3 and MC4 receptors and a stable agonist concerning the modulation of food intake. This view is compatible with the finding that underweight and normal-weight children have higher circulating plasma α-MSH levels compared with obese children.40


2.1. Ghrelin elicits food intake

Ghrelin is an endogenous ligand for growth hormone (GH) secretagogue receptors (GHS-R). It potently stimulates GH secretion and ghrelin-immunoreactive neurons in the hypothalamic arcuate nucleus.41,42 Acyl ghrelin activates tGHS-Rs on neuropeptide Y/agouti-related protein (NPY/AgRP) neurons in arcuate nuclei and releases NPY and AgRP to stimulate food intake, body weight gain,43–48 and diabetic hyperphagia (Figure).49,50 Chemical ablation and double knockout of NPY and AgRP attenuates ghrelin-induced increased food intake.51,52 However, a single knockout NPY mouse model features preserved the AgRP activity, which partially compensates for the decreased ghrelin-induced food intake.52 ICV administration of AgRP is a competitive antagonist of MCRs,53 and acts to increase feeding.33 AgRP is also a potent antagonist of MC receptors in weight control.54,55

Fig. 1
Fig. 1:
Schematic diagram depicts the activation of distinct neuroendocrine signaling by acyl ghrelin from the stomach and the effects of biological activities on food intake, small intestinal motility, and fecal pellet output colonic secretion through MC3 and MC4 receptors. AgRP, agouti-related protein; Arc, arcuate nucleus; CART, cocaine- and amphetamine-regulated transcript; GHS-R, secretagogue receptors; MCR, melanocortin receptor; MSH, melanocyte stimulating hormone; NPY, neuropeptide Y; PMOC, proopiomelanocortin.

2.2 α-MSH attenuates ghrelin-elicited food intake

In rats allowed to feed ad libitum, the plasma acyl ghrelin concentration is reportedly low and reaches a peak during fasting,56,57 followed by a rapid decrease to the nadir level after intake.58 ICV injection of ghrelin can rapidly stimulate increased food intake.59 The effect can persist for 8 h59–61 but has ceased by 12 or 24 h (Table 1).60,61 ICV administration of α-MSH to rats (1.0 and 2.0 nmol/rat) significantly suppresses the ghrelin-induced increased food intake 2 h after injection.61,62 The suppression can persist for 8 h after injection61 with an apparent dose-dependent effect (1–6 nmol/rat),27 although no effect is evident at 24 h after injection (Table).27,61 α-MSH, which displays high affinity to the MC3 and MC4 receptors, can competitively activate the MC receptors with AgRP that is stimulated by ghrelin, and can partly attenuate the effect of acyl ghrelin on food intake.61,62

Table 1
Table 1:
Acyl Ghrelin-induced food intake


3.1. Ghrelin elicits gastric emptying

Ghrelin reportedly increases gastric emptying in conscious food-deprived rats63,64 and humans.61,65,66 ICV administration of ghrelin can increase gastric motility in a dose-dependent manner.67 However, this was not apparent in totally vagotomized rats.67 Ghrelin induces orexigenic effects by means of vagal nerve and afferent activities,68 and is a very powerful gastrokinetic agent. ICV injection of Ghrelin can induce c-fos expression in the nucleus tractus solitaries and the dorsomotor nucleus of the vagus,69 and can directly stimulate the enteric neural pathway.70

The ICV injection of ghrelin also potently stimulates feeding behavior and increases gastric emptying by activating hypothalamic NPY/AgRP neurons in arcuate nuclei.56,68 However, in rats the ICV administration of NPY suppresses postprandial antral contraction71 and delays gastric emptying.71,72 No effect on gastric emptying in humans has been observed.73 These results might hint that ghrelin-NPY signaling is not the cause of acceleration of gastric emptying.49 ICV injection of AgRP can increase feeding33 through MCR53 but the influence of AgRP on gastric motility is unknown.

Central ICV49,68 or peripheral (intravenous70,74 or intraperitoneal68) administration of ghrelin can dramatically accelerate gastric emptying. Obesity and overeating are closely linked to rapid gastric emptying. On the contrary, anorexia and cachexia are related to delayed gastric emptying.75,76 Ghrelin is a strong prokinetic agent and may be the basis of a potent method to reverse postoperative gastric ileus.74

3.2. α-MSH fails to attenuate gastric emptying elicited by ghrelin

α-MSH acting in a competitive role with AgRP on MC3 and MC4 receptors does not attenuate the gastric emptying that is accelerated by central acyl ghrelin stimulation.61 These results indicate that the accelerated gastric emptying induced by the ICV injection of ghrelin is not mediated by MCRs in the brain.


4.1. Ghrelin elicits small intestinal transit

Ghrelin introduced by ICV injection61 and intravenous injection70,74 increases the geometric center of intestinal transit and running percentage of small intestinal transit.61 The intraperitoneal injection of ghrelin and oral administration of ghrelin receptor agonist also accelerate small intestinal transit.48 Ghrelin acts on the receptors in the intestinal neuromuscular tissue to accelerate the intestinal transit via cholinergic mechanisms.77 The acceleration of small intestinal transit can be affected upon the down-regulation of GHS-R1a in small intestinal muscle layers.78 The intraperitoneal injection of ghrelin is able to normalize the burn-induced79 and diabetic-related80 delay in intestinal transit. The intravenous injection of ghrelin can reverse postoperative gastric ileus in rats.74

4.2 α-MSH fails to attenuate ghrelin-elicited small intestinal transit

α-MSH acts on the MC4 receptor, which is highly enriched in peptide YY expressing enteroendocrine L cells, to induce the release of peptide YY.24 The intravenous administration of peptide YY inhibits intestinal transit.81,82 A study in rats reported that the ICV injection of α-MSH at a dose of 2 nmol/rat attenuated the increase in the geometric center, induced by ghrelin ICV injection, but not the running percentage in small intestinal transit.61 These results offer support for the view that central acyl ghrelin accelerates the small intestinal transit at least in part via MC receptors in the brain.


5.1. Ghrelin elicits colonic transit

ICV injection of ghrelin can accelerate colonic transit time61,83,84 and can increase fecal pellet output.61,83 Intravenous injection of ghrelin does not have these effects.74 Intraperitoneal injection of ghrelin does not accelerate colonic transit,80 but does increase fecal output.48 Central administration of ghrelin can moderate gastrointestinal motor functions at paraventricular nuclei mediated by NPY1- and CRF1 receptor-dependent mechanisms.85 Central or peripheral administration of NPY1 receptor antagonist can attenuate the ghrelin-induced increase of colonic transit.84,86 The effect of central acyl ghrelin on colonic motor functions through the action of AgRP on MC receptors is still uninvestigated.

5.2. α-MSH partly attenuates ghrelin-elicited colonic transit

α-MSH displays high affinity to the MC3 and MC4 receptors. It does not attenuate the accelerated colonic transit induced by ICV injection of ghrelin.61 However, α-MSH decreases the increases in fecal pellet and total fecal weight that are induced by ICV injection of ghrelin.61 These findings imply that distal colonic motility and secretion, similar to fecal pellet and total fecal weight, are partly mediated by MC receptors in the brain.

In conclusion, central-ghrelin-induced acceleration of gastric emptying is not mediated by MCRs, but the acceleration of the small intestinal transit at least is partly via MCRs in the brain. Distal colonic motility and secretion, similar to fecal pellet and total fecal weight, is partly mediated by MCRs in the brain. The various interplays between acyl ghrelin and MCRs may provide a new therapeutic avenue for ameliorating anorexia and constipation.

Previous Presentations: Parts of the content were presented at the Asian Pacific Digestive Week in Kobe, Japan on November 5, 2016.


1. Bloom F, Battenberg E, Rossier J, Ling N, Guillemin R. Neurons containing beta-endorphin in rat brain exist separately from those containing enkephalin: immunocytochemical studies.Proc Natl Acad Sci U S A1978751591–5
2. Bloom FE, Battenberg EL, Shibasaki T, Benoit R, Ling N, Guillemin R. Localization of gamma-melanocyte stimulating hormone (gamma MSH) immunoreactivity in rat brain and pituitary.Regul Pept19801205–22
3. Jacobowitz DM, O’Donohue TL. alpha-Melanocyte stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain.Proc Natl Acad Sci U S A1978756300–4
4. Cone RD, Lu D, Koppula S, Vage DI, Klungland H, Boston B, et al. The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation.Recent Prog Horm Res199651287–317
5. Gantz I, Konda Y, Tashiro T, Shimoto Y, Miwa H, Munzert G, et al. Molecular cloning of a novel melanocortin receptor.J Biol Chem19932688246–50
6. Gantz I, Miwa H, Konda Y, Shimoto Y, Tashiro T, Watson SJ, et al. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor.J Biol Chem199326815174–9
7. Griffon N, Mignon V, Facchinetti P, Diaz J, Schwartz JC, Sokoloff P. Molecular cloning and characterization of the rat fifth melanocortin receptor.Biochem Biophys Res Commun19942001007–14
8. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors.Science19922571248–51
9. Roselli-Rehfuss L, Mountjoy KG, Robbins LS, Mortrud MT, Low MJ, Tatro JB, et al. Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system.Proc Natl Acad Sci U S A1993908856–60
10. Xia Y, Wikberg JE, Chhajlani V. Expression of melanocortin 1 receptor in periaqueductal gray matter.Neuroreport199562193–6
11. Schiöth HB, Muceniece R, Larsson M, Wikberg JE. The melanocortin 1, 3, 4 or 5 receptors do not have a binding epitope for ACTH beyond the sequence of alpha-MSH.J Endocrinol199715573–8
12. Kask A, Mutulis F, Muceniece R, Pähkla R, Mutule I, Wikberg JE, et al. Discovery of a novel superpotent and selective melanocortin-4 receptor antagonist (HS024): evaluation in vitro and in vivo.Endocrinology19981395006–14
13. Xia Y, Wikberg JE. Localization of ACTH receptor mRNA by in situ hybridization in mouse adrenal gland.Cell Tissue Res199628663–8
14. Schiöth HB, Chhajlani V, Muceniece R, Klusa V, Wikberg JE. Major pharmacological distinction of the ACTH receptor from other melanocortin receptors.Life Sci199659797–801
15. Chhajlani V. Distribution of cDNA for melanocortin receptor subtypes in human tissues.Biochem Mol Biol Int19963873–80
16. Butler AA, Kesterson RA, Khong K, Cullen MJ, Pelleymounter MA, Dekoning J, et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse.Endocrinology20001413518–21
17. Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, Yu H, et al. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.Nat Genet20002697–102
18. Marsh DJ, Hollopeter G, Huszar D, Laufer R, Yagaloff KA, Fisher SL, et al. Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides.Nat Genet199921119–22
19. Chen AS, Metzger JM, Trumbauer ME, Guan XM, Yu H, Frazier EG, et al. Role of the melanocortin-4 receptor in metabolic rate and food intake in mice.Transgenic Res20009145–54
20. Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain.Mol Endocrinol199481298–308
21. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice.Cell199788131–41
22. Vaisse C, Clement K, Guy-Grand B, Froguel P. A frameshift mutation in human MC4R is associated with a dominant form of obesity.Nat Genet199820113–4
23. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O’Rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity.Nat Genet199820111–2
24. Panaro BL, Tough IR, Engelstoft MS, Matthews RT, Digby GJ, Møller CL, et al. The melanocortin-4 receptor is expressed in enteroendocrine L cells and regulates the release of peptide YY and glucagon-like peptide 1 in vivo.Cell Metab2014201018–29
25. Kask A, Rägo L, Mutulis F, Pähkla R, Wikberg JE, Schiöth HB. Selective antagonist for the melanocortin 4 receptor (HS014) increases food intake in free-feeding rats.Biochem Biophys Res Commun199824590–3
26. Harrold JA, Widdowson PS, Williams G. Altered energy balance causes selective changes in melanocortin-4(MC4-R), but not melanocortin-3 (MC3-R), receptors in specific hypothalamic regions: further evidence that activation of MC4-R is a physiological inhibitor of feeding.Diabetes199948267–71
27. Lucas N, Legrand R, Ouelaa W, Breton J, Tennoune N, Bole-Feysot C, et al. Effects of rabbit anti-α-melanocyte-stimulating hormone (α-MSH) immunoglobulins on α-MSH signaling related to food intake control.Neuropeptides20144821–7
28. Gantz I, Shimoto Y, Konda Y, Miwa H, Dickinson CJ, Yamada T. Molecular cloning, expression, and characterization of a fifth melanocortin receptor.Biochem Biophys Res Commun19942001214–20
29. Fathi Z, Iben LG, Parker EM. Cloning, expression, and tissue distribution of a fifth melanocortin receptor subtype.Neurochem Res199520107–13
30. Chen W, Kelly MA, Opitz-Araya X, Thomas RE, Low MJ, Cone RD. Exocrine gland dysfunction in MC5-R-deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides.Cell199791789–98
31. Delbende C, Jegou S, Tranchand-Bunel D, Leroux P, Tonon MC, Mocaër E, et al. Role of alpha-MSH and related peptides in the central nervous system.Rev Neurol (Paris)1985141429–39
32. Eskay RL, Giraud P, Oliver C, Brown-Stein MJ. Distribution of alpha-melanocyte-stimulating hormone in the rat brain: evidence that alpha-MSH-containing cells in the arcuate region send projections to extrahypothalamic areas.Brain Res197917855–67
33. Rossi M, Kim MS, Morgan DG, Small CJ, Edwards CM, Sunter D, et al. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo.Endocrinology19981394428–31
34. Tsujii S, Bray GA. Acetylation alters the feeding response to MSH and beta-endorphin.Brain Res Bull198923165–9
35. Zheng H, Patterson LM, Phifer CB, Berthoud HR. Brain stem melanocortinergic modulation of meal size and identification of hypothalamic POMC projections.Am J Physiol Regul Integr Comp Physiol2005289R247–58
36. Jonsson L, Skarphedinsson JO, Skuladottir GV, Atlason PT, Eiriksdottir VH, Franzson L, et al. Melanocortin receptor agonist transiently increases oxygen consumption in rats.Neuroreport2001123703–8
37. Adan RA, Szklarczyk AW, Oosterom J, Brakkee JH, Nijenhuis WA, Schaaper WM, et al. Characterization of melanocortin receptor ligands on cloned brain melanocortin receptors and on grooming behavior in the rat.Eur J Pharmacol1999378249–58
38. Ludwig DS, Mountjoy KG, Tatro JB, Gillette JA, Frederich RC, Flier JS, et al. Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus.Am J Physiol1998274E627–33
39. Lucas N, Legrand R, Breton J, Déchelotte P, Edwards-Lévy F, Fetissov SO. Chronic delivery of α-melanocyte-stimulating hormone in rat hypothalamus using albumin-alginate microparticles: effects on food intake and body weight.Neuroscience2015290445–53
40. Vehapoğlu A, Türkmen S, Terzioğlu Ş. Alpha-melanocyte-stimulating hormone and agouti-related protein: do they play a role in appetite regulation in childhood obesity?J Clin Res Pediatr Endocrinol2016840–7
41. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach.Nature1999402656–60
42. Chen CY, Inui A, Asakawa A, Fujino K, Kato I, Chen CC, et al. Des-acyl ghrelin acts by CRF type 2 receptors to disrupt fasted stomach motility in conscious rats.Gastroenterology20051298–25
43. Seoane LM, López M, Tovar S, Casanueva FF, Señarís R, Diéguez C. Agouti-related peptide, neuropeptide Y, and somatostatin-producing neurons are targets for ghrelin actions in the rat hypothalamus.Endocrinology2003144544–51
44. Mondal MS, Date Y, Yamaguchi H, Toshinai K, Tsuruta T, Kangawa K, et al. Identification of ghrelin and its receptor in neurons of the rat arcuate nucleus.Regul Pept200512655–9
45. Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I. Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression.Endocrinology20001414797–800
46. 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.Diabetes2001502438–43
47. Wang L, Saint-Pierre DH, Taché Y. Peripheral ghrelin selectively increases Fos expression in neuropeptide Y - synthesizing neurons in mouse hypothalamic arcuate nucleus.Neurosci Lett200232547–51
48. Charoenthongtrakul S, Giuliana D, Longo KA, Govek EK, Nolan A, Gagne S, et al. Enhanced gastrointestinal motility with orally active ghrelin receptor agonists.J Pharmacol Exp Ther20093291178–86
49. Verhulst PJ, De Smet B, Saels I, Thijs T, Ver Donck L, Moechars D, et al. Role of ghrelin in the relationship between hyperphagia and accelerated gastric emptying in diabetic mice.Gastroenterology20081351267–76
50. Chen CY, Fujimiya M, Laviano A, Chang FY, Lin HC, Lee SD. Modulation of ingestive behavior and gastrointestinal motility by ghrelin in diabetic animals and humans.J Chin Med Assoc201073225–9
51. Tamura H, Kamegai J, Shimizu T, Ishii S, Sugihara H, Oikawa S. Ghrelin stimulates GH but not food intake in arcuate nucleus ablated rats.Endocrinology20021433268–75
52. Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, Frazier EG, et al. Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein.Endocrinology20041452607–12
53. Hagan MM, Rushing PA, Pritchard LM, Schwartz MW, Strack AM, Van Der Ploeg LH, et al. Long-term orexigenic effects of AgRP-(83---132) involve mechanisms other than melanocortin receptor blockade.Am J Physiol Regul Integr Comp Physiol2000279R47–52
54. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.Science1997278135–8
55. Shutter JR, Graham M, Kinsey AC, Scully S, Lüthy R, Stark KL. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice.Genes Dev199711593–602
56. Guo ZF, Ren AJ, Zheng X, Qin YW, Cheng F, Zhang J, et al. Different responses of circulating ghrelin, obestatin levels to fasting, re-feeding and different food compositions, and their local expressions in rats.Peptides2008291247–54
57. Kirchner H, Gutierrez JA, Solenberg PJ, Pfluger PT, Czyzyk TA, Willency JA, et al. GOAT links dietary lipids with the endocrine control of energy balance.Nat Med200915741–5
58. Liu J, Prudom CE, Nass R, Pezzoli SS, Oliveri MC, Johnson ML, et al. Novel ghrelin assays provide evidence for independent regulation of ghrelin acylation and secretion in healthy young men.J Clin Endocrinol Metab2008931980–7
59. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, et al. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion.Endocrinology20001414325–8
60. Chen CY, Tsai CY, Lee WJ, Liaw WJ, Chiang CH, Ho ST, et al. Intracerebroventricular O-n-octanoylated ghrelin and its splice variant-induced feeding is blocked by insulin, independent of obestatin or CRF receptor, in satiated rats.Nutrition201228812–20
61. Huang HH, Chen LY, Doong ML, Chang SC, Chen CY. α-melanocyte stimulating hormone modulates the central acyl ghrelin-induced stimulation of feeding, gastrointestinal motility, and colonic secretion.Drug Des Devel Ther2017112377–86
62. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding.Nature2001409194–8
63. Chen CY, Doong ML, Chien EJ, Luo JC, Lu CL, Lin HC, et al. Intracerebroventricular ghrelin enhances non-nutrient semiliquid gastric emptying in fasted conscious rats.Gastroenterol J Taiwan200825242–8
64. Yeh C, Ting CH, Doong ML, Chi CW, Lee SD, Chen CY. Intracerebroventricular urocortin 3 counteracts central acyl ghrelin-induced hyperphagic and gastroprokinetic effects via CRF receptor 2 in rats.Drug Des Devel Ther2016103281–90
65. Levin F, Edholm T, Schmidt PT, Grybäck P, Jacobsson H, Degerblad M, et al. Ghrelin stimulates gastric emptying and hunger in normal-weight humans.J Clin Endocrinol Metab2006913296–302
66. Falkén Y, Webb DL, Abraham-Nordling M, Kressner U, Hellström PM, Näslund E. Intravenous ghrelin accelerates postoperative gastric emptying and time to first bowel movement in humans.Neurogastroenterol Motil201325474–80
67. Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, et al. Ghrelin stimulates gastric acid secretion and motility in rats.Biochem Biophys Res Commun2000276905–8
68. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, et al. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin.Gastroenterology2001120337–45
69. Date Y, Nakazato M, Murakami N, Kojima M, Kangawa K, Matsukura S. Ghrelin acts in the central nervous system to stimulate gastric acid secretion.Biochem Biophys Res Commun2001280904–7
70. Fukuda H, Mizuta Y, Isomoto H, Takeshima F, Ohnita K, Ohba K, et al. Ghrelin enhances gastric motility through direct stimulation of intrinsic neural pathways and capsaicin-sensitive afferent neurones in rats.Scand J Gastroenterol2004391209–14
71. Ishiguchi T, Amano T, Matsubayashi H, Tada H, Fujita M, Takahashi T. Centrally administered neuropeptide Y delays gastric emptying via Y2 receptors in rats.Am J Physiol Regul Integr Comp Physiol2001281R1522–30
72. Matsuda M, Aono M, Moriga M, Okuma M. Centrally administered neuropeptide Y (NPY) inhibits gastric emptying and intestinal transit in the rat.Dig Dis Sci199338845–50
73. Allen JM, Fitzpatrick ML, Yeats JC, Darcy K, Adrian TE, Bloom SR. Effects of peptide YY and neuropeptide Y on gastric emptying in man.Digestion198430255–62
74. Trudel L, Tomasetto C, Rio MC, Bouin M, Plourde V, Eberling P, et al. Ghrelin/motilin-related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat.Am J Physiol Gastrointest Liver Physiol2002282G948–52
75. Duggan JP, Booth DA. Obesity, overeating, and rapid gastric emptying in rats with ventromedial hypothalamic lesions.Science1986231609–11
76. Inui A. Cancer anorexia-cachexia syndrome: are neuropeptides the key?Cancer Res1999594493–501
77. Edholm T, Levin F, Hellström PM, Schmidt PT. Ghrelin stimulates motility in the small intestine of rats through intrinsic cholinergic neurons.Regul Pept200412125–30
78. Yang CG, Qiu WC, Wang ZG, Yu S, Yan J, Zheng Q. Down-regulation of ghrelin receptors in the small intestine delays small intestinal transit in vagotomized rats.Mol Med Rep201141061–5
79. Sallam HS, Oliveira HM, Gan HT, Herndon DN, Chen JD. Ghrelin improves burn-induced delayed gastrointestinal transit in rats.Am J Physiol Regul Integr Comp Physiol2007292R253–7
80. Qiu WC, Wang ZG, Lv R, Wang WG, Han XD, Yan J, et al. Ghrelin improves delayed gastrointestinal transit in alloxan-induced diabetic mice.World J Gastroenterol2008142572–7
81. Savage AP, Adrian TE, Carolan G, Chatterjee VK, Bloom SR. Effects of peptide YY (PYY) on mouth to caecum intestinal transit time and on the rate of gastric emptying in healthy volunteers.Gut198728166–70
82. Lin HC, Neevel C, Chen JH. Slowing intestinal transit by PYY depends on serotonergic and opioid pathways.Am J Physiol Gastrointest Liver Physiol2004286G558–63
83. Huang HH, Ting CH, Syu YF, Chang SC, Chen CY. Correlation between colonic secretion and colonic motility in rats: Role of ghrelin.World J Gastroenterol20162210140–7
84. Tebbe JJ, Tebbe CG, Mronga S, Ritter M, Schäfer MK. Central neuropeptide Y receptors are involved in 3rd ventricular ghrelin induced alteration of colonic transit time in conscious fed rats.BMC Gastroenterol200555
85. Tebbe JJ, Mronga S, Tebbe CG, Ortmann E, Arnold R, Schäfer MK. Ghrelin-induced stimulation of colonic propulsion is dependent on hypothalamic neuropeptide Y1- and corticotrophin-releasing factor 1 receptor activation.J Neuroendocrinol200517570–6
86. Tough IR, Forbes S, Tolhurst R, Ellis M, Herzog H, Bornstein JC, et al. Endogenous peptide YY and neuropeptide Y inhibit colonic ion transport, contractility and transit differentially via Y1 and Y2 receptors.Br J Pharmacol2011164471–84

Acyl ghrelin; Alpha-melanocyte stimulating hormone; Colonic transit time; Fecal pellet output; Food intake; Gastric emptying; Intracerebroventricular; Small intestinal transit

© 2019 by Lippincott Williams & Wilkins, Inc.