ghrelin, appetite and gastric electrical stimulation

P

R1

G2

S3

a4b5

6

a7

8

A9

R10

R11

A12

A13

14

K15

G16

P17

F18

H19

S20

E21

N22

C23

24

25

26

27

28

29

30

31

32

33

34

35

36

137

38

r39

[40

p41

G

B3

0d

ARTICLE IN PRESSG ModelEP 68401 1–7

Peptides xxx (2011) xxx–xxx

Contents lists available at ScienceDirect

Peptides

j ourna l ho me pa ge: www.elsev ier .com/ locate /pept ides

eview

hrelin, appetite and gastric electrical stimulation

yrine Gallasa,b, Sergueï O. Fetissova,∗

Digestive System & Nutrition Laboratory (ADEN EA4311), Rouen University, IFR23, Rouen 76183, FrancePhysiology Laboratory, Faculty of Medicine of Monastir, Monastir 5019, Tunisia

r t i c l e i n f o

rticle history:eceived 13 January 2011eceived in revised form 26 May 2011ccepted 27 May 2011vailable online xxx

eywords:

a b s t r a c t

Ghrelin is a peptide hormone produced mainly by the stomach and has widespread physiologicalfunctions including increase in appetite. The stimulation of the ghrelin system represents a potentialtherapeutic approach in various disorders characterized by deficient ghrelin signaling or by low appetite.This stimulation may be achieved via pharmacological targeting of the ghrelin receptor with syntheticghrelin or ghrelin mimetics or via increased endogenous ghrelin production. Recently, it was demon-strated that gastric electrical stimulation (GES) with Enterra parameters results in increased ghrelin

Please cite this article in press as: Gallas S, Fetissov SO. Ghrelin, appetite and gastric electrical stimulation. Peptides (2011),doi:10.1016/j.peptides.2011.05.027

ut–brain axiseptide hormonesood intakeungeratietyating disordersatural autoantibodies

production in rats. Furthermore, recent data revealed putative role of ghrelin-reactive immunoglobulinsin the modulation of the ghrelin signaling which can be also stimulated by GES. Here, we review the linksbetween GES and ghrelin in existing GES experimental and clinical applications for treatment of gastro-paresis, functional dyspepsia or obesity and discuss if GES can be proposed as a non-pharmacologicalapproach to improve ghrelin secretion in several pathological conditions characterized by low appetite,such as anorexia nervosa or anorexia–cachexia syndrome.

© 2011 Published by Elsevier Inc.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. GES improves appetite in gastroparesis and functional dyspepsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003. GES stimulates ghrelin production in experimental models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004. Cellular network activated by GES and ghrelin-reactive IgG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005. GES in obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006. Potential applications of GES to stimulate ghrelin production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

6.1. Functional dyspepsia and gastroparesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006.2. Anorexia nervosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006.3. Anorexia–cachexia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Introduction

Ghrelin is a peptide hormone discovered in 1999 as the natu-al ligand for the growth hormone secretagogue receptor (GHSR)59]. It is a 28-amino acid motilin-related peptide producedredominantly by the enteroendocrine cells of gastric mucosa.hrelin displays a strong growth hormone (GH)-releasing activity,

∗ Corresponding author at: ADEN Laboratory, Faculté de Médecine-Pharmacie, 22,ld Gambetta, Rouen 76183, Cedex 1, France. Tel.: +33 02 35 14 84 55; fax: +33 025 14 82 26.

E-mail address: [email protected] (S.O. Fetissov).

42

plays an important role in the stimulation of appetite, reg- 43

ulates energy homeostasis, stimulates gastrointestinal motility, 44

suppresses inflammation and has effects on central nervous system 45

functions [12,42,60]. These widespread physiological functions had 46

encouraged research in order to assess the efficacy of exogenous 47

ghrelin administration as a novel therapy in different disorders 48

such as GH deficiency, cachexia, anorexia nervosa, gastroparesis, 49

functional dyspepsia or cancer anorexia. 50

Gastric electrical stimulation (GES) has become a treatment 51

option for patients with gastroparesis, functional dyspepsia and 52

obesity and its effects on appetite were also noticed. Recent studies 53

have demonstrated that GES may also modulate ghrelin production. 54

Thus, we review here the links between GES and ghrelin and discuss 55

196-9781/$ – see front matter © 2011 Published by Elsevier Inc.oi:10.1016/j.peptides.2011.05.027

dx.doi.org/10.1016/j.peptides.2011.05.027


http://www.sciencedirect.com/science/journal/01969781

http://www.elsevier.com/locate/peptides

mailto:[email protected]



ARTICLE IN PRESSG ModelPEP 68401 1–7

2 S. Gallas, S.O. Fetissov / Peptides xxx (2011) xxx–xxx

if GES can be proposed as a non-pharmacological approach in order56

to modulate ghrelin production in several pathological conditions.57

2. GES improves appetite in gastroparesis and functional58

dyspepsia59

Recently, GES has been used as a therapeutic option in medically60

refractory gastroparesis of diabetic, postvagotomy and idiopathic61

etiologies [1,38]. GES with an implantable stimulator (Enterra ther-62

apy, by Medtronic Inc.) has been approved in 2000 by the US Food63

and Drug Administration (Humanitarian Device Exemption) [2].64

In Europe, the device received CE mark in 2002. The Enterra gas-65

tric stimulation system is implanted surgically, by laparotomy or66

laparoscopy. A pair of electrodes is implanted in the muscular layer67

of the body of the stomach, along the greater curvature, approxi-68

mately 10 cm from the pylorus. The two leads are then connected to69

the pulse generator, placed in a subcutaneous pocket in the anterior70

abdominal wall. Stimulation parameters typically used are ampli-71

tude of 5 mA, a pulse width of 330 �s, a frequency of 14 Hz, and a72

cycle of 0.1 s on and 5.0 s off.73

Gastroparesis is a chronic disorder characterized by delayed gas-74

tric emptying of solids without evidence of mechanical obstruction75

[89]. Symptoms of gastroparesis are variable and include mainly76

early satiety, nausea, vomiting and bloating [88]. Functional dys-77

pepsia is a functional gastro-duodenal disorder characterized by78

postprandial fullness and early satiety [107]. Patients with gas-79

troparesis or functional dyspepsia experience usually alteration80

of nutritional status, poor quality of life and high healthcare81

cost [2,102,110]. Current treatment is based mainly on dietary82

manipulation, prokinetics and anti-emetics drugs [90]. In med-83

ically refractory nausea and vomiting related to gastroparesis 84

or to functional dyspepsia, numerous studies demonstrated that 85

GES results in more than 50% improvement of several symp- 86

toms including appetite, nausea and vomiting giving patients a 87

better nutritional status and a more satisfactory quality of life 88

[1,4,10,44,51,69,70,75,95]. 89

3. GES stimulates ghrelin production in experimental 90

models 91

Although the mechanisms underlying all GES-mediated clinical 92

effects have not been fully elucidated, increased ghrelin production 93

may explain improved appetite among several other symptoms. In 94

fact, it has recently been demonstrated, that 1 h of GES in rats results 95

in a significant increase in the number of ghrelin positive cells in 96

the stomach, in ghrelin mRNA expression as well as in plasma ghre- 97

lin levels providing the evidence for increased ghrelin production 98

(Fig. 1) [48]. Such GES-induced increase in gastric and plasma ghre- 99

lin may result in ghrelin action locally as well as systemically. In the 100

stomach, ghrelin displays prokinetic effect which is an important 101

factor for gastroparesis treatment [120]. Indeed, ghrelin admin- 102

istration in diabetic patients with gastroparesis increased gastric 103

emptying [34,79]. The prokinetic action of ghrelin can be medi- 104

ated by gastric myenteric neurons which express ghrelin receptors 105

[23,128] and also by central routes [8]. However, several experi- 106

mental or clinical studies did not find significant increase of gastric 107

emptying after GES and no correlations between the improvement 108

of symptoms and the rates of gastric emptying under GES therapy 109

were noted [1,10,16,44,51,68,70]. The ability of ghrelin to regulate 110

appetite independently of gastric emptying was also shown in rats 111

Fig. 1. Effect of GES on ghrelin immunoreactivity in the rat gastric mucosa in the activated ventral portion (A. control vs. B. GES) and in the dorsal portion (C. control vs. D.GES). (E) Mean number of ghrelin positive cells per field. (F) Effect of GES on ghrelin, PYY, and GLP1 mRNA expression in the rat stomach, the duodenum, and the ileum,respectively. (G) Effect of GES on plasma ghrelin levels in rats. Data are expressed as mean ± SEM. *p < 0.05 vs. control group. Scale bar (A–D), 100 �m. The bar legends arethe same for E–G.

Reproduced from [48].



S. Gallas, S.O. Fetissov / Peptides xxx (2011) xxx–xxx 3

Fig. 2. Double immunostaining of c-Fos (green) and ghrelin (red) in rat gastricQ3m[r

r112

a113

g114

m115

s116

a117

s118

b119

i120

h121

s122

r123

s124

l125

n126

d127

w128

i129

4130

I131

132

a133

i134

i135

e136

d137

a138

k139

G140

h141

g142

i143

n144

W145

G146

w147

i148

m149

p150

I151

t152

c153

Fig. 3. Effects of GES on plasma levels of ghrelin-reactive IgG autoantibodies inrats after 1 h of GES with Enterra parameters. For GES experimental procedure see[48]. Plasma levels (OD, optical density in ELISA) of IgG autoAbs reactive with acyl-ghrelin were higher in the GES group vs. control rats corresponding to 400% increase(Student’s t-test, p = 0.02,). The levels of IgG autoAbs reactive with des-acyl ghrelin

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

ucosa after 1 h of GES with Enterra parameters. For experimental procedure see48]. (For interpretation of the references to color in this figure legend, the reader iseferred to the web version of the article.)

eceiving ghrelin receptor antagonist [36]. Ghrelin may stimulateppetite via suppression of firing on vagal afferents that expresshrelin receptor [24] or via a hormonal route. In our view, the hor-onal route of the GES-induced ghrelin effects on central nervous

ystem may underlie its orexigenic effects. In fact, GES-inducedctivation of hypothalamic agouti-related protein (AgRP) expres-ion was shown in rats [48] while orexigenic effect of ghrelin cane dependent on AgRP neurons [111,121]. GES-induced reduction

n the activity of corticotropin-releasing hormone neurons in theypothalamic paraventricular nucleus [50], one of the AgRP down-tream targets, may participate in the central ghrelin-mediatedesponses leading to increased appetite and reduced activity of thetress axis. Thus, it is likely that GES-induced secretion of ghre-in may be a key factor underlying improvement of appetite andutritional status in GES patients with gastroparesis or functionalyspepsia. Nevertheless, it will be of importance to verify if GESith Enterra parameters will result in increased ghrelin secretion

n humans as well.

. Cellular network activated by GES and ghrelin-reactivegG

As revealed in a rat model of GES with Enterra parameters, 1 hfter GES an increased number of c-Fos positive cells was detectedn the gastric mucosal and submucosal layers [48]. The c-Fos pos-tive cells, however, were largely distinct from ghrelin-producingnteroendocrine cells suggesting c-Fos-independent ghrelin pro-uction (Fig. 2). In fact, the c-Fos activated cells were identifieds mucosal lymphoid cells such as lymphocytes or plasmocytesnown to produce immunoglobulins [48]. This finding suggests thatES-associated functional effects may also involve modulation ofumoral immunity. To explore if such response may be relevant tohrelin signaling, we measured plasma levels of ghrelin-reactivemmunoglobulins. Such immunoglobulins or autoantibodies areormally present in plasma of healthy subjects and rats [40].e found that 1 h after GES, plasma levels of immunoglobulins

(IgG) reactive with acyl-ghrelin but not with des-acyl-ghrelinere higher that in control rats (Fig. 3). These data suggest that

n response to GES, ghrelin-reactive IgG may participate in theodulation of ghrelin signaling together with increased ghrelin

Please cite this article in press as: Gallas S, Fetissov SO. Ghrelindoi:10.1016/j.peptides.2011.05.027

roduction. Such modulation may include a role of ghrelin-reactivegG as ghrelin peptide transporters as was suggested for autoan-ibodies reactive with other peptide hormones [52]. This findingan be relevant to the potential use of GES to increase appetite in

were not significantly affected by GES (Student’s t-test, p = 0.18). Data are expressedas mean ± SEM. *p < 0.05 vs. control group. For the ghrelin-reactive autoAbs assaysee [117].

pathological conditions characterized by anorexia and chronically

elevated ghrelin levels such as anorexia nervosa (see Section 6.2). In

fact, recent study showed that serum levels of acyl-ghrelin-reactive

IgG were lower in patients with restrictive anorexia nervosa, impli-

cating them in the state of apparent ghrelin resistance [117]. It is

therefore possible that GES-induced concomitant increase in ghre-

lin and ghrelin-reactive IgG may be optimal for the activation of

ghrelin targets in the brain and efficient stimulation of appetite.

5. GES in obesity

The parameters of GES in obesity are different from that in gas-

troparesis. The stimulus method used in obesity is called Transcend

Implantable Gastric Stimulator (Medtronic) and delivers a train on-

time 2 s, off-time 3 s, pulse frequency 40 Hz, width 180–400 �s and

amplitude 6–10 mA. The electrodes are sutured in the lesser cur-

vature of the stomach, 6 cm proximal to the pylorus [17,22,25].

Several studies reported that GES in morbid obesity reduces pre-

prandial appetite and increases satiety resulting in weight loss from

21% to 30% of the excess body weight at six to nine months after

implantation [17,22,25]. Although GES is able to produce an anorex-

igenic effect in obese patients, the underlying mechanisms are

incompletely understood [15]. It was observed that GES had signifi-

cant effects on neuronal activities in the brain [94,103,114,115,129]and on the plasma levels [18,127] of several peptide hormones

including leptin, cholecystokinin (CCK), glucagon-like peptide-1

(GLP1), somatostatin and insulin. In rats, 2 h of GES was demon-

strated to reduce ghrelin expression in the hypothalamus [71,131].

The data from clinical studies reporting effects of GES in obesity on

plasma ghrelin levels are inconsistent. Two studies failed to demon-

strate significant GES effects on ghrelin levels [25,98]. However, in

morbidly obese patients one study showed a significant increase

of plasma ghrelin six months after GES which was interpreted as a

physiological response of ghrelin associated with body weight loss

[19].

6. Potential applications of GES to stimulate ghrelin

production

Ghrelin is the only known peripheral orexigenic peptide hor-

mone suggesting that stimulation of the ghrelin system can beparticularly suited as a therapeutic target for improving appetite in

pathological conditions associated with anorexia and cachexia [56].

, appetite and gastric electrical stimulation. Peptides (2011),

This stimulation may be achieved via pharmacological approaches 193

aiming the ghrelin receptor directly or via stimulation of endoge- 194

nous ghrelin production. The recent data showing that GES with 195

Enterra parameters results in increased ghrelin production in rats 196




Table 1Plasma ghrelin concentrations in several pathological conditions.

Increased ghrelin concentration Decreased ghrelin concentration

Anorexia nervosa [77,87,93,101] Obesity [122,132]Bulimia-nervosa [61,112,113] Diabetes [13,92]Chronic heart failure cachexia

[84,126]Gastric by pass [21,62,78,119]

Cancer anorexia [49,108] Parkinson’s disease [43,123]Kidney failure [14,55,116] Chronic obstructive pulmonary disease

[197

o198

a199

e200

t201

e202

S203

s204

E205

t206

s207

p208

l209

w210

t211

212

v213

i214

d215

c216

r217

g218

s219

s220

i221

s222

c223

c224

[225

b226

6227

228

v229

[230

c231

t232

l233

s234

ghrelin response to feeding [6,47] and a loss of rhythmicity in the 235

plasma ghrelin levels [6] were also shown. 236

The use of ghrelin to treat these gastrointestinal disorders was 237

suggested based on its effects on gastric motility and secretion 238

[26,30,33,46,58,74,91,120,122,128]. Although there are sequence 239

similarities between ghrelin and motilin, a gastrointestinal hor- 240

mone with a known ability to enhance gastric motility, and between 241

the GHSR and the motilin receptor [7], the gastro-prokinetic effect 242

of ghrelin seems to be not mediated through the release of motilin 243

[105]. This prokinetic activity is also independent of the GH releas- 244

ing effect [66]. Thus, ghrelin was shown to enhance gastric motility 245

and gastric emptying in rats and mice [30,32,58,74], to accelerate 246

small intestinal transit [33] and to reverse postoperative gastric 247

ileus [45,120] and septic ileus [26]. 248

Administration of physiological doses of exogenous ghrelin to 249

humans does not significantly alter gastric motility [20,96]. How- 250

ever intravenously administration of high doses (40 �g) in healthy 251

volunteers induces a premature gastric phase III of the migrating 252

motor complex as well as inducing an increase in the proximal 253

stomach tone [105]. These observations had suggested ghrelin as a 254

potential prokinetic drug in gastrointestinal motility disorders such 255

as gastroparesis or postoperative ileus. Thus, several studies have 256

shown that infusion of ghrelin as opposed to placebo accelerates 257

gastric emptying and decreased meal-related symptoms in patients 258

with gastroparesis [34,79,106]. In addition, repeated intravenous 259

infusions of ghrelin (3 �g/kg) twice a day to five patients with func- 260

tional dyspepsia for 2 weeks tended to increase daily food intake by 261

approximately 30% in comparison to levels before and after ghrelin 262

treatment [3]. In this study, hunger sensation was significantly ele- 263

vated at the end of ghrelin administration. Thus, although GES has 264

been already used for treatment of functional dyspepsia and gastro- 265

paresis, the knowledge that increased ghrelin production might be 266

one of the underlying causes of effective GES therapy may provide 267

additional indications for its use in these conditions, particularly 268

for improvement of the nutritional status. 269

6.2. Anorexia nervosa 270

Anorexia nervosa is an eating disorder characterized by chronic 271

energy deficit and reduced food intake [37]. Although neuro- 272

biology of anorexia nervosa was extensively studied showing 273

alterations in the main neurotransmitter systems [57], the com- 274

mon etiology and the final common pathways have not been yet 275

determined. Nevertheless, recent data suggest that altered pep- 276

tidergic signaling, normally involved in regulation of appetite, 277

might underlie anorexia and bulimia nervosa via pathological 278

action of neuropeptide-reactive autoantibodies [39,41]. Increased 279

plasma levels of ghrelin that normalized after weight recovery 280

were repeatedly shown in subjects with restrictive anorexia ner- 281

TG

(COPD) [72]Prader–Willi syndrome [9,35]

48], allowed us to propose the potential use of GES in vari-us pathological conditions associated with ghrelin deficiency orpparent ghrelin resistance (Table 1). The interest in increasingndogenous ghrelin secretion by GES will be encouraged for mainlyhe following reasons: first, clinical trials demonstrated positiveffects of GES treatment on disease symptoms and quality of life.econd, long-term follow-up studies proved sustained efficacy,afety and few side effects of GES such as in 211 patients withnterra therapy followed for 10 years [75]. The limits of the GESreatment are mainly the cost of the device and the need for itsurgical implantation. However, the development of temporaryercutaneous GES [5], which is a less invasive procedure than

aparotomy, will be an alternative method in acute conditions andill help to select patients who might ultimately benefit from long-

erm implantations of electrical stimulator.Pharmacological ghrelin mimetics use may have some disad-

antages. First, the high cost and the need of repeated intravenousnjection are impractical for a long-term use. Second, long-termata on safety, efficacy and quality of life are still lacking sincelinical trials of ghrelin agonists are limited to phase II, as summa-ized in Table 2 [29]. In these circumstances, increasing endogenoushrelin secretion might reduce the risk of overdose and associatedide effects of exogenous ghrelin or ghrelin mimetics. Moreover,ince an increase of plasma ghrelin was found after weight lossn obesity [19], it is highly unlikely that GES-induced endogenoustimulation of ghrelin may result in hyperphagia and obesity. Inontrast, other favorable effects of ghrelin including improved glu-ose control [97,104], gastric motility [91], cardiovascular function82], anti-inflammatory [31,67] and anxiolytic responses [73] cane expected.

.1. Functional dyspepsia and gastroparesis

The data on plasma ghrelin in functional dyspepsia are contro-ersial showing decreased [65,99], normal [100,109] or increased63] levels as compared to healthy controls. These conflicting dataan be related to heterogeneous symptoms in patients with func-


ional dyspepsia. In fact, it was demonstrated that plasma ghrelinevels were correlated with symptom scores in functional dyspep-ia [100]. Moreover, in patients with gastroparesis an abnormal

vosa [77,87,93,101]. The reduced food intake in anorexia nervosa 282

despite chronically increased ghrelin levels has led to consider 283

these patients insensitive or resistant to ghrelin [11,76]. In fact, 284

able 2hrelin agonists [29].

Drug Company Target Status

EX-1314, oral Elixir Pharmaceuticals Cancer cachexiaGastroprokinetic

Preclinical finished

RC-1291, oral Sapphire Therapeutics Cancer anorexiaCachexia

Phase II

TZP-101, iv Tranzyme Pharmaceuticals Postoperative ileusSevere gastroparesis

Phase IIb

TZP-102, oral Tranzyme Pharmaceuticals Chronic gastroparesisOther gastrointestinal motility disorders

Phase I

Ipamorelin, iv Sapphire Therapeutics Postoperative ileus Phase I/IIRC-1141, oral Sapphire Therapeutics Opioid-induced bowel dysfunction Pre-IND





pharmacological ghrelin administration in patients with anorexia285

nervosa does not induce appetite and food intake as observed in286

healthy controls [11,76] although some improvement was reported287

in one pilot study [53]. This situation suggests that apparent ghrelin288

resistance in anorexia nervosa is not absolute and can be over-289

come with sufficient stimulation of the ghrelin system. Increasing290

endogenous ghrelin production by GES may thus represent a poten-291

tial therapeutic approach to improve appetite in subjects with292

anorexia nervosa.293

6.3. Anorexia–cachexia294

Cachexia is a syndrome characterized by severe body weight, fat295

and muscle loss and increased protein catabolism due to underlying296

disease resulting in increased patients’ morbidity and mortal-297

ity [80]. Anorexia and reduced food intake are common during298

cachexia further deteriorating nutritional status and which bio-299

logical mechanisms are not yet completely understood [64,118].300

Cachexia may occur in various chronic diseases such as cancer,301

chronic heart failure or chronic kidney disease [124]. Most studies302

reported increased ghrelin levels in cachexia (Table 1) compared303

with healthy controls or noncachectic patients with the same304

underlying diseases [54,84,108,130]. This suggests that chronically305

increased plasma ghrelin may represent a state of ghrelin resistance306

in the anorexia–cachexia syndrome similarly to anorexia nervosa.307

Acute and chronic administrations of ghrelin in rodent models308

of cachexia were shown to increase feeding and body weight309

[27,28,85]. This response was associated with increased expression310

of hypothalamic orexigenic peptides (AgRP and neuropeptide Y)311

and decreased inflammatory markers [28]. This suggests the ghre-312

lin agonists may be useful for treatment of anorexia–cachexia [27].313

Indeed, clinical studies with ghrelin agonists have demonstrated314

increased food intake and body weight in cachectic patients with315

various etiologies of underlying chronic diseases [81,83,86,125].316

However, the short half-time of ghrelin in circulation and the317

necessity of repeated injections for a long period in such chronic318

conditions could limit its large use for anorexia–cachexia treat-319

ment. Thus, GES-induced ghrelin secretion may be proposed as a320

potential solution for the stimulation of the ghrelin system in these321

patients.322

7. Conclusion323

The effects of GES to increase ghrelin production as seen in324

acute animal experiments are promising considering broad benefi-325

cial effects associated with activation of the ghrelin system. Beside326

clinically validated long-term efficacy of GES in dyspepsia and327

gastroparesis, potential clinical conditions that may benefit from328

GES with parameters which would increase ghrelin production are329

represented by states characterized by anorexia and cachexia. Nev-330

ertheless, further studies are necessary in order to validate the331

clinical use of GES for increasing ghrelin production.332

Acknowledgements333

The authors would like to thank Prof. P. Déchelotte (Rouen Uni-334

versity, France) and Prof. A. Inui (Kagoshima University, Japan) for335

their support as well as Dr. M. Terashi for performing ELISA tests336

on ghrelin-reactive autoantibodies.337

ReferencesQ1338

[1] Abell T, McCallum R, Hocking M, Koch K, Abrahamsson H, Leblanc I, et al.339

Gastric electrical stimulation for medically refractory gastroparesis. Gas-340

troenterology 2003;125:421–8.341

[2] Abell TL, Bernstein RK, Cutts T, Farrugia G, Forster J, Hasler WL, et al. Treatment 342

of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil 343

2006;18:263–83. 344

[3] Akamizu T, Iwakura H, Ariyasu H, Hosoda H, Murayama T, Yokode M, et al. 345

Repeated administration of ghrelin to patients with functional dyspepsia: its 346

effects on food intake and appetite. Eur J Endocrinol 2008;158:491–8. 347

[4] Anand C, Al-Juburi A, Familoni B, Rashed H, Cutts T, Abidi N, et al. Gastric 348

electrical stimulation is safe and effective: a long-term study in patients 349

with drug-refractory gastroparesis in three regional centers. Digestion 350

2007;75:83–9. 351

[5] Andersson S, Ringstrom G, Elfvin A, Simren M, Lonroth H, Abrahamsson H. 352

Temporary percutaneous gastric electrical stimulation: a novel technique Q2 353

tested in patients with non-established indications for gastric electrical stim- 354

ulation. Digestion 2011;83:3–12. 355

[6] Asai S, Katabami T, Obi N, Matsui T, Kato H, Obi R, et al. No ghrelin response to 356

oral glucose in diabetes mellitus with gastroparesis. Endocr J 2009;56:79–87. 357

[7] Asakawa A, Inui A, Fujimiya M, Sakamaki R, Shinfuku N, Ueta Y, et al. Stom- 358

ach regulates energy balance via acylated ghrelin and desacyl ghrelin. Gut 359

2005;54:18–24. 360

[8] Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, et al. Ghrelin is 361

an appetite-stimulatory signal from stomach with structural resemblance to 362

motilin. Gastroenterology 2001;120:337–45. 363

[9] Bizzarri C, Rigamonti AE, Luce A, Cappa M, Cella SG, Berini J, et al. Children 364

with Prader–Willi syndrome exhibit more evident meal-induced responses 365

in plasma ghrelin and peptide YY levels than obese and lean children. Eur J 366

Endocrinol 2010;162:499–505. 367

[10] Brody F, Vaziri K, Saddler A, Ali A, Drenon E, Hanna B, et al. Gastric electrical 368

stimulation for gastroparesis. J Am Coll Surg 2008;207:533–8. 369

[11] Broglio F, Gianotti L, Destefanis S, Fassino S, Abbate Daga G, Mondelli V, et al. 370

The endocrine response to acute ghrelin administration is blunted in patients 371

with anorexia nervosa, a ghrelin hypersecretory state. Clin Endocrinol (Oxf) 372

2004;60:592–9. 373

[12] Castaneda TR, Tong J, Datta R, Culler M, Tschöp MH. Ghrelin in the regulation 374

of body weight and metabolism. Front Neuroendocrinol 2010;31:44–60. 375

[13] Celi F, Bini V, Papi F, Santilli E, Ferretti A, Mencacci M, et al. Circulating acylated 376

and total ghrelin and galanin in children with insulin-treated type 1 diabetes: 377

relationship to insulin therapy, metabolic control and pubertal development. 378

Clin Endocrinol (Oxf) 2005;63:139–45. 379

[14] Chang CC, Hung CH, Yen CS, Hwang KL, Lin CY. The relationship of plasma 380

ghrelin level to energy regulation, feeding and left ventricular function in non- 381

diabetic haemodialysis patients. Nephrol Dial Transplant 2005;20:2172–7. 382

[15] Chen J. Mechanisms of action of the implantable gastric stimulator for obesity. 383

Obes Surg 2004;14(Suppl. 1):S28–32. 384

[16] Chen JD, Qian L, Ouyang H, Yin J. Gastric electrical stimulation with short 385

pulses reduces vomiting but not dysrhythmias in dogs. Gastroenterology 386

2003;124:401–9. 387

[17] Cigaina V. Long-term follow-up of gastric stimulation for obesity: the Mestre 388

8-year experience. Obes Surg 2004;14(Suppl. 1):S14–22. 389

[18] Cigaina V, Hirschberg AL. Gastric pacing for morbid obesity: plasma levels of 390

gastrointestinal peptides and leptin. Obes Res 2003;11:1456–62. 391

[19] Cigaina V, Hirschberg AL. Plasma ghrelin and gastric pacing in morbidly obese 392

patients. Metabolism 2007;56:1017–21. 393

[20] Cremonini F, Camilleri M, Vazquez Roque M, McKinzie S, Burton D, Baxter K, 394

et al. Obesity does not increase effects of synthetic ghrelin on human gastric 395

motor functions. Gastroenterology 2006;131:1431–9. 396

[21] Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, et al. 397

Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. 398

N Engl J Med 2002;346:1623–30. 399

[22] Dargent J. Surgical treatment of morbid obesity by adjustable gastric band: 400

the case for a conservative strategy in the case of failure—a 9-year series. Obes 401

Surg 2004;14:986–90. 402

[23] Dass NB, Munonyara M, Bassil AK, Hervieu GJ, Osbourne S, Corcoran S, et al. 403

Growth hormone secretagogue receptors in rat and human gastrointestinal 404

tract and the effects of ghrelin. Neuroscience 2003;120:443–53. 405

[24] Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, et al. The 406

role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth 407

hormone secretion in rats. Gastroenterology 2002;123:1120–8. 408

[25] De Luca M, Segato G, Busetto L, Favretti F, Aigner F, Weiss H, et al. Progress in 409

implantable gastric stimulation: summary of results of the European multi- 410

center study. Obes Surg 2004;14(Suppl. 1):S33–9. 411

[26] De Winter BY, De Man JG, Seerden TC, Depoortere I, Herman AG, Peeters TL, 412

et al. Effect of ghrelin and growth hormone-releasing peptide 6 on septic ileus 413

in mice. Neurogastroenterol Motil 2004;16:439–46. 414

[27] DeBoer MD. Emergence of ghrelin as a treatment for cachexia syndromes. 415

Nutrition 2008;24:806–14. 416

[28] DeBoer MD, Zhu XX, Levasseur P, Meguid MM, Suzuki S, Inui A, et al. Ghrelin 417

treatment causes increased food intake and retention of lean body mass in a 418

rat model of cancer cachexia. Endocrinology 2007;148:3004–12. 419

[29] Depoortere I. Targeting the ghrelin receptor to regulate food intake. Regul 420

Pept 2009;156:13–23. 421

[30] Depoortere I, De Winter B, Thijs T, De Man J, Pelckmans P, Peeters T. Com- 422

parison of the gastroprokinetic effects of ghrelin, GHRP-6 and motilin in rats 423

in vivo and in vitro. Eur J Pharmacol 2005;515:160–8. 424

[31] Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, Palaniappan R, et al. 425

Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine 426

expression by human monocytes and T cells. J Clin Invest 2004;114:57–66. 427





[32] Dornonville de la Cour C, Lindstrom E, Norlen P, Hakanson R. Ghrelin stim-428

ulates gastric emptying but is without effect on acid secretion and gastric429

endocrine cells. Regul Pept 2004;120:23–32.430

[33] Edholm T, Levin F, Hellstrom PM, Schmidt PT. Ghrelin stimulates motility in431

the small intestine of rats through intrinsic cholinergic neurons. Regul Pept432

2004;121:25–30.433

[34] Ejskjaer N, Vestergaard ET, Hellstrom PM, Gormsen LC, Madsbad S, Madsen434

JL, et al. Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in435

adults with diabetes and symptomatic gastroparesis. Aliment Pharmacol Ther436

2009;29:1179–87.437

[35] Erdie-Lalena CR, Holm VA, Kelly PC, Frayo RS, Cummings DE. Ghrelin levels in438

young children with Prader–Willi syndrome. J Pediatr 2006;149:199–204.439

[36] Esler WP, Rudolph J, Claus TH, Tang W, Barucci N, Brown S-E, et al. Small-440

molecule ghrelin receptor antagonists improve glucose tolerance, suppress441

appetite, and promote weight loss. Endocrinology 2007;148:5175–85.442

[37] Fairburn CG, Harrison PJ. Eating disorders. Lancet 2003;361:407–16.443

[38] Familoni BO, Abell TL, Nemoto D, Voeller G, Salem A, Gabor O. Electrical stim-444

ulation at a frequency higher than basal rate in human stomach. Dig Dis Sci445

1997;42:885–91.446

[39] Fetissov SO, Déchelotte P. The putative role of neuropeptide autoantibodies447

in anorexia nervosa. Curr Opin Clin Nutr Metab Care 2008;11:428–34.448

[40] Fetissov SO, Hamze Sinno M, Coëffier M, Bole-Feysot C, Ducrotté P,449

Hökfelt T, et al. Autoantibodies against appetite-regulating peptide hor-450

mones and neuropeptides: putative modulation by gut microflora. Nutrition451

2008;24:348–59.452

[41] Fetissov SO, Hamze Sinno M, Coquerel Q, Do Rego JC, Coëffier M, Gilbert D, et al.453

Emerging role of autoantibodies against appetite-regulating neuropeptides in454

eating disorders. Nutrition 2008;24:854–9.455

[42] Fetissov SO, Laviano A, Kalra S, Inui A. Update on ghrelin. Int J Pept 2010.456

[43] Fiszer U, Michalowska M, Baranowska B, Wolinska-Witort E, Jeske W, Jethon457

M, et al. Leptin and ghrelin concentrations and weight loss in Parkinson’s458

disease. Acta Neurol Scand 2010;121:230–6.459

[44] Forster J, Sarosiek I, Lin Z, Durham S, Denton S, Roeser K, et al. Further experi-460

ence with gastric stimulation to treat drug refractory gastroparesis. Am J Surg461

2003;186:690–5.462

[45] Fraser GL, Venkova K, Hoveyda HR, Thomas H, Greenwood-Van Meerveld B.463

Effect of the ghrelin receptor agonist TZP-101 on colonic transit in a rat model464

of postoperative ileus. Eur J Pharmacol 2009;604:132–7.465

[46] Fujino K, Inui A, Asakawa A, Kihara N, Fujimura M, Fujimiya M. Ghrelin induces466

fasted motor activity of the gastrointestinal tract in conscious fed rats. J Phys-467

iol 2003;550:227–40.468

[47] Gaddipati KV, Simonian HP, Kresge KM, Boden GH, Parkman HP. Abnormal469

ghrelin and pancreatic polypeptide responses in gastroparesis. Dig Dis Sci470

2006;51:1339–46.471

[48] Gallas S, Sinno MH, Boukhettala N, Coëffier M, Dourmap N, Gourcerol472

G, et al. Gastric electrical stimulation increases ghrelin production and473

inhibits catecholaminergic brainstem neurons in rats. Eur J Neurosci 2011;33:474

276–84.475

[49] Garcia JM, Garcia-Touza M, Hijazi RA, Taffet G, Epner D, Mann D, et al. Active476

ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia. J477

Clin Endocrinol Metab 2005;90:2920–6.478

[50] Gourcerol G, Gallas S, Mounien L, Leblanc I, Bizet P, Boutelet I, et al. Gas-479

tric electrical stimulation modulates hypothalamic corticotropin-releasing480

factor-producing neurons during post-operative ileus in rat. Neuroscience481

2007;148:775–81.482

[51] Gourcerol G, Leblanc I, Leroi AM, Denis P, Ducrotte P. Gastric electrical stim-483

ulation in medically refractory nausea and vomiting. Eur J Gastroenterol484

Hepatol 2007;19:29–35.485

[52] Hamze Sinno M, Do Rego JC, Coëffier M, Bole-Feysot C, Ducrotte P, Gilbert D,486

et al. Regulation of feeding and anxiety by �-MSH reactive autoantibodies.487

Psychoneuroendocrinology 2009;34:140–9.488

[53] Hotta M, Ohwada R, Akamizu T, Shibasaki T, Takano K, Kangawa K. Ghrelin489

increases hunger and food intake in patients with restricting-type anorexia490

nervosa: a pilot study. Endocr J 2009;56:1119–28.491

[54] Itoh T, Nagaya N, Yoshikawa M, Fukuoka A, Takenaka H, Shimizu Y, et al. Ele-492

vated plasma ghrelin level in underweight patients with chronic obstructive493

pulmonary disease. Am J Respir Crit Care Med 2004;170:879–82.494

[55] Jarkovska Z, Rosicka M, Krsek M, Sulkova S, Haluzik M, Justova V, et al.495

Plasma ghrelin levels in patients with end-stage renal disease. Physiol Res496

2005;54:403–8.497

[56] Kamiji MM, Inui A. The role of ghrelin and ghrelin analogues in wasting dis-498

ease. Curr Opin Clin Nutr Metab Care 2008;11:443–51.499

[57] Kaye WH, Fudge JL, Paulus M. New insights into symptoms and neurocircuit500

function of anorexia nervosa. Nat Rev Neurosci 2009;10:573–84.501

[58] Kitazawa T, De Smet B, Verbeke K, Depoortere I, Peeters TL. Gastric motor502

effects of peptide and non-peptide ghrelin agonists in mice in vivo and in503

vitro. Gut 2005;54:1078–84.504

[59] Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghre-505

lin is a growth-hormone-releasing acylated peptide from stomach. Nature506

1999;402:656–60.507

[60] Kojima M, Kangawa K. Structure and function of ghrelin. Orphan G protein-508

coupled receptors and novel neuropeptides. Heidelberg: Springer Berlin;509

2008. p. 89–115.510

[61] Kojima S, Nakahara T, Nagai N, Muranaga T, Tanaka M, Yasuhara D, et al.511

Altered ghrelin and peptide YY responses to meals in bulimia nervosa. Clin512

Endocrinol (Oxf) 2005;62:74–8.513

[62] Korner J, Bessler M, Cirilo LJ, Conwell IM, Daud A, Restuccia NL, et al. Effects 514

of Roux-en-Y gastric bypass surgery on fasting and postprandial concentra- 515

tions of plasma ghrelin, peptide YY, and insulin. J Clin Endocrinol Metab 516

2005;90:359–65. 517

[63] Lanzini A, Magni P, Petroni ML, Motta M, Lanzarotto F, Villanacci V, et al. 518

Circulating ghrelin level is increased in coeliac disease as in functional dys- 519

pepsia and reverts to normal during gluten-free diet. Aliment Pharmacol Ther 520

2006;23:907–13. 521

[64] Laviano A, Meguid MM, Inui A, Muscaritoli M, Rossi-Fanelli F. Therapy insight: 522

cancer anorexia–cachexia syndrome—when all you can eat is yourself. Nat 523

Clin Prac Oncol 2005;2:158–65. 524

[65] Lee KJ, Cha DY, Cheon SJ, Yeo M, Cho SW. Plasma ghrelin levels and their rela- 525

tionship with gastric emptying in patients with dysmotility-like functional 526

dyspepsia. Digestion 2009;80:58–63. 527

[66] Levin F, Edholm T, Schmidt PT, Gryback P, Jacobsson H, Degerblad M, et al. 528

Ghrelin stimulates gastric emptying and hunger in normal-weight humans. J 529

Clin Endocrinol Metab 2006;91:3296–302. 530

[67] Li WG, Gavrila D, Liu X, Wang L, Gunnlaugsson S, Stoll LL, et al. Ghrelin inhibits 531

proinflammatory responses and nuclear factor-kappaB activation in human 532

endothelial cells. Circulation 2004;109:2221–6. 533

[68] Lin Z, Hou Q, Sarosiek I, Forster J, McCallum RW. Association between changes 534

in symptoms and gastric emptying in gastroparetic patients treated with 535

gastric electrical stimulation. Neurogastroenterol Motil 2008;20:464–70. 536

[69] Lin Z, McElhinney C, Sarosiek I, Forster J, McCallum R. Chronic gastric electrical 537

stimulation for gastroparesis reduces the use of prokinetic and/or antiemetic 538

medications and the need for hospitalizations. Dig Dis Sci 2005;50:1328–34. 539

[70] Lin Z, Sarosiek I, Forster J, McCallum RW. Symptom responses, long-term out- 540

comes and adverse events beyond 3 years of high-frequency gastric electrical 541

stimulation for gastroparesis. Neurogastroenterol Motil 2006;18:18–27. 542

[71] Liu S, Tang M, Tao S, Chen JD. Central expressions of ghrelin and cholecys- 543

tokinin in rats with gastric electrical stimulation. Obes Surg 2008;18:109–14. 544

[72] Luo F-M, Liu X-J, Li S-Q, Wang Z-L, Liu C-T, Yuan Y-M. Circulating ghre- 545

lin in patients with chronic obstructive pulmonary disease. Nutrition 546

2005;21:793–8. 547

[73] Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, 548

et al. The orexigenic hormone ghrelin defends against depressive symptoms 549

of chronic stress. Nat Neurosci 2008;11:752–3. 550

[74] Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, et al. Ghrelin 551

stimulates gastric acid secretion and motility in rats. Biochem Biophys Res 552

Commun 2000;276:905–8. 553

[75] McCallum RW, Lin Z, Forster J, Roeser K, Hou Q, Sarosiek I. Gastric electrical 554

stimulation improves outcomes of patients with gastroparesis for up to 10 555

years. Clin Gastroenterol Hepatol 2011;9, 314–9 e1. 556

[76] Miljic D, Pekic S, Djurovic M, Doknic M, Milic N, Casanueva FF, et al. Ghre- 557

lin has partial or no effect on appetite, growth hormone, prolactin, and 558

cortisol release in patients with anorexia nervosa. J Clin Endocrinol Metab 559

2006;91:1491–5. 560

[77] Misra M, Miller KK, Tsai P, Gallagher K, Lin A, Lee N, et al. Elevated peptide 561

YY levels in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab 562

2005, jc.2005-1878. 563

[78] Morinigo R, Casamitjana R, Moize V, Lacy AM, Delgado S, Gomis R, et al. Short- 564

term effects of gastric bypass surgery on circulating ghrelin levels. Obes Res 565

2004;12:1108–16. 566

[79] Murray CDR, Martin NM, Patterson M, Taylor SA, Ghatei MA, Kamm MA, et al. 567

Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, 568

placebo controlled, crossover study. Gut 2005;54:1693–8. 569

[80] Muscaritoli M, Anker SD, Argilés J, Aversa Z, Bauer JM, Biolo G, et al. 570

Consensus definition of sarcopenia, cachexia and pre-cachexia: joint doc- 571

ument elaborated by Special Interest Groups (SIG) “cachexia–anorexia in 572

chronic wasting diseases” and “nutrition in geriatrics”. Clin Nutr 2010;29: 573

154–9. 574

[81] Nagaya N, Itoh T, Murakami S, Oya H, Uematsu M, Miyatake K, et al. Treatment 575

of cachexia with ghrelin in patients with COPD. Chest 2005;128:1187–93. 576

[82] Nagaya N, Miyatake K, Uematsu M, Oya H, Shimizu W, Hosoda H, et al. Hemo- 577

dynamic, renal, and hormonal effects of ghrelin infusion in patients with 578

chronic heart failure. J Clin Endocrinol Metab 2001;86:5854–9. 579

[83] Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W, et al. 580

Effects of ghrelin administration on left ventricular function, exercise capac- 581

ity, and muscle wasting in patients with chronic heart failure. Circulation 582

2004;110:3674–9. 583

[84] Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Okumura H, et al. Ele- 584

vated circulating level of ghrelin in cachexia associated with chronic heart 585

failure: relationships between ghrelin and anabolic/catabolic factors. Circu- 586

lation 2001;104:2034–8. 587

[85] Nagaya N, Uematsu M, Kojima M, Ikeda Y, Yoshihara F, Shimizu W, et al. 588

Chronic administration of ghrelin improves left ventricular dysfunction and 589

attenuates development of cardiac cachexia in rats with heart failure. Circu- 590

lation 2001;104:1430–5. 591

[86] Neary NM, Small CJ, Wren AM, Lee JL, Druce MR, Palmieri C, et al. Ghrelin 592

increases energy intake in cancer patients with impaired appetite: acute, ran- 593

domized, placebo-controlled trial. J Clin Endocrinol Metab 2004;89:2832–6. 594

[87] Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, et al. 595

Weight gain decreases elevated plasma ghrelin concentrations of patients 596

with anorexia nervosa. Eur J Endocrinol 2001;145:669–73. 597

[88] Park MI, Camilleri M. Gastroparesis: clinical update. Am J Gastroenterol 598

2006;101:1129–39. 599





[89] Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Associa-600

tion medical position statement: diagnosis and treatment of gastroparesis.601

Gastroenterology 2004;127:1589–91.602

[90] Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association603

technical review on the diagnosis and treatment of gastroparesis. Gastroen-604

terology 2004;127:1592–622.605

[91] Peeters TL. Ghrelin: a new player in the control of gastrointestinal functions.606

Gut 2005;54:1638–49.607

[92] Poykko SM, Kellokoski E, Horkko S, Kauma H, Kesaniemi YA, Ukkola O. Low608

plasma ghrelin is associated with insulin resistance, hypertension, and the609

prevalence of type 2 diabetes. Diabetes 2003;52:2546–53.610

[93] Prince AC, Brooks SJ, Stahl D, Treasure J. Systematic review and meta-analysis611

of the baseline concentrations and physiologic responses of gut hormones to612

food in eating disorders. Am J Clin Nutr 2009;89:755–65.613

[94] Qin C, Sun Y, Chen JD, Foreman RD. Gastric electrical stimulation modu-614

lates neuronal activity in nucleus tractus solitarii in rats. Auton Neurosci615

2005;119:1–8.616

[95] Reddymasu SC, Lin Z, Sarosiek I, Forster J, McCallum RW. Efficacy of gas-617

tric electrical stimulation in improving functional vomiting in patients with618

normal gastric emptying. Dig Dis Sci 2009.619

[96] Sanger GJ. Motilin, ghrelin and related neuropeptides as targets for the treat-620

ment of GI diseases. Drug Discov Today 2008;13:234–9.621

[97] Sangiao-Alvarellos S, Cordido F. Effect of ghrelin on glucose–insulin home-622

ostasis: therapeutic implications. Int J Pept 2010:2010.623

[98] Sanmiguel CP, Haddad W, Aviv R, Cunneen SA, Phillips EH, Kapella W, et al.624

The TANTALUS system for obesity: effect on gastric emptying of solids and625

ghrelin plasma levels. Obes Surg 2007;17:1503–9.626

[99] Shindo T, Futagami S, Hiratsuka T, Horie A, Hamamoto T, Ueki N, et al. Compar-627

ison of gastric emptying and plasma ghrelin levels in patients with functional628

dyspepsia and non-erosive reflux disease. Digestion 2009;79:65–72.629

[100] Shinomiya T, Fukunaga M, Akamizu T, Irako T, Yokode M, Kangawa K, et al.630

Plasma acylated ghrelin levels correlate with subjective symptoms of func-631

tional dyspepsia in female patients. Scand J Gastroenterol 2005;40:648–53.632

[101] Soriano-Guillen L, Barrios V, Campos-Barros A, Argente J. Ghrelin levels in633

obesity and anorexia nervosa: effect of weight reduction or recuperation. J634

Pediatr 2004;144:36–42.635

[102] Soykan I, Sivri B, Sarosiek I, Kiernan B, McCallum RW. Demography, clinical636

characteristics, psychological and abuse profiles, treatment, and long-term637

follow-up of patients with gastroparesis. Dig Dis Sci 1998;43:2398–404.638

[103] Sun X, Tang M, Zhang J, Chen JD. Excitatory effects of gastric electrical stimula-639

tion on gastric distension responsive neurons in ventromedial hypothalamus640

(VMH) in rats. Neurosci Res 2006;55:451–7.641

[104] Sun Y, Asnicar M, Smith RG. Central and peripheral roles of ghrelin on glucose642

homeostasis. Neuroendocrinology 2007;86:215–28.643

[105] Tack J, Depoortere I, Bisschops R, Delporte C, Coulie B, Meulemans A, et al.644

Influence of ghrelin on interdigestive gastrointestinal motility in humans.645

Gut 2006;55:327–33.646

[106] Tack J, Depoortere I, Bisschops R, Verbeke K, Janssens J, Peeters T. Influence647

of ghrelin on gastric emptying and meal-related symptoms in idiopathic gas-648

troparesis. Aliment Pharmacol Ther 2005;22:847–53.649

[107] Tack J, Talley NJ, Camilleri M, Holtmann G, Hu P, Malagelada JR, et al. Func-650

tional gastroduodenal disorders. Gastroenterology 2006;130:1466–79.651

[108] Takahashi M, Terashima M, Takagane A, Oyama K, Fujiwara H, Wakabayashi652

G. Ghrelin and leptin levels in cachectic patients with cancer of the digestive653

organs. Int J Clin Oncol 2009;14:315–20.654

[109] Takamori K, Mizuta Y, Takeshima F, Akazawa Y, Isomoto H, Ohnita K,655

et al. Relation among plasma ghrelin level, gastric emptying, and psycho-656

logic condition in patients with functional dyspepsia. J Clin Gastroenterol657

2007;41:477–83.658

[110] Talley NJ, Weaver AL, Zinsmeister AR. Impact of functional dyspepsia on qual-659

ity of life. Dig Dis Sci 1995;40:584–9.660

[111] Tamura H, Kamegai J, Shimizu T, Ishii S, Sugihara H, Oikawa S. Ghrelin stim-661

ulates GH but not food intake in arcuate nucleus ablated rats. Endocrinology662

2002;143:3268–75.663

[112] Tanaka M, Naruo T, Muranaga T, Yasuhara D, Shiiya T, Nakazato M, et al. 664

Increased fasting plasma ghrelin levels in patients with bulimia nervosa. Eur 665

J Endocrinol 2002;146:R1–3. 666

[113] Tanaka M, Naruo T, Yasuhara D, Tatebe Y, Nagai N, Shiiya T, et al. Fasting 667

plasma ghrelin levels in subtypes of anorexia nervosa. Psychoneuroen- 668

docrinology 2003;28:829–35. 669

[114] Tang M, Zhang J, Chen J. Central mechanisms of gastric electrical stimulation 670

involving neurons in the paraventricular nucleus of the hypothalamus in rats. 671

Obes Surg 2006;16:344–52. 672

[115] Tang M, Zhang J, Xu L, Chen JD. Implantable gastric stimulation alters expres- 673

sion of oxytocin- and orexin-containing neurons in the hypothalamus of rats. 674

Obes Surg 2006;16:762–9. 675

[116] Tentolouris N, Makrilakis K, Doulgerakis D, Moyssakis I, Kokkinos A, Kyriaki D, 676

et al. Increased plasma ghrelin levels in chronic renal failure are not associated 677

with hemodynamic parameters. Horm Metab Res 2005;37:646–52. 678

[117] Terashi M, Asakawa A, Harada T, Ushikai M, Coquerel Q, Sinno MH, et al. 679

Ghrelin reactive autoantibodies in restrictive anorexia nervosa. Nutrition 680

2011;27:407–13. 681

[118] Tisdale MJ. Biology of cachexia. J Natl Cancer Inst 1997;89:1763–73. 682

[119] Tritos NA, Mun E, Bertkau A, Grayson R, Maratos-Flier E, Goldfine A. Serum 683

ghrelin levels in response to glucose load in obese subjects post-gastric bypass 684

surgery. Obes Res 2003;11:919–24. 685

[120] Trudel L, Tomasetto C, Rio MC, Bouin M, Plourde V, Eberling P, et al. 686

Ghrelin/motilin-related peptide is a potent prokinetic to reverse gas- 687

tric postoperative ileus in rat. Am J Physiol Gastrointest Liver Physiol 688

2002;282:G948–52. 689

[121] Tschop M, Flora DB, Mayer JP, Heiman ML. Hypophysectomy prevents ghrelin- 690

induced adiposity and increases gastric ghrelin secretion in rats. Obes Res 691

2002;10:991–9. 692

[122] Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman 693

ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 694

2001;50:707–9. 695

[123] Unger MM, Moller JC, Mankel K, Eggert KM, Bohne K, Bodden M, et al. Post- 696

prandial ghrelin response is reduced in patients with Parkinson’s disease and 697

idiopathic REM sleep behaviour disorder: a peripheral biomarker for early 698

Parkinson’s disease? J Neurol 2010. 699

[124] von Haehling S, Anker SD. Cachexia as a major underestimated and unmet 700

medical need: facts and numbers. J Cachexia Sarcopenia Muscle 2010;1:1–5. 701

[125] Wynne K, Giannitsopoulou K, Small CJ, Patterson M, Frost G, Ghatei 702

MA, et al. Subcutaneous ghrelin enhances acute food intake in malnour- 703

ished patients who receive maintenance peritoneal dialysis: a randomized, 704

placebo-controlled trial. J Am Soc Nephrol 2005;16:2111–8. 705

[126] Xin X, Ren AJ, Zheng X, Qin YW, Zhao XX, Yuan WJ, et al. Disturbance of cir- 706

culating ghrelin and obestatin in chronic heart failure patients especially in 707

those with cachexia. Peptides 2009;30:2281–5. 708

[127] Xing JH, Lei Y, Ancha HR, Harty RF, Chen JD. Effect of acute gastric electrical 709

stimulation on the systemic release of hormones and plasma glucose in dogs. 710

Dig Dis Sci 2007;52:495–501. 711

[128] Xu L, Depoortere I, Tomasetto C, Zandecki M, Tang M, Timmermans J-P, et al. 712

Evidence for the presence of motilin, ghrelin, and the motilin and ghrelin 713

receptor in neurons of the myenteric plexus. Regul Pep 2005;124:119–25. 714

[129] Xu L, Sun X, Lu J, Tang M, Chen JD. Effects of gastric electric stimulation 715

on gastric distention responsive neurons and expressions of CCK in rodent 716

hippocampus. Obesity (Silver Spring) 2008;16:951–7. 717

[130] Yoshimoto A, Mori K, Sugawara A, Mukoyama M, Yahata K, Suganami T, et al. 718

Plasma ghrelin and desacyl ghrelin concentrations in renal failure. J Am Soc 719

Nephrol 2002;13:2748–52. 720

[131] Zhang J, Liu S, Tang M, Chen JD. Optimal locations and parameters of gastric 721

electrical stimulation in altering ghrelin and oxytocin in the hypothalamus of 722

rats. Neurosci Res 2008;62:262–9. 723

[132] Zwirska-Korczala K, Konturek SJ, Sodowski M, Wylezol M, Kuka D, Sowa 724

P, et al. Basal and postprandial plasma levels of PYY, ghrelin, cholecys- 725

tokinin, gastrin and insulin in women with moderate and morbid obesity 726

and metabolic syndrome. J Physiol Pharmacol 2007;58(Suppl. 1):13–35. 727


ghrelin, appetite and gastric electrical stimulation

Documents