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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 8 4521-4524
Copyright © 2005 by The Endocrine Society

Ghrelin Does Not Stimulate Food Intake in Patients with Surgical Procedures Involving Vagotomy

C. W. le Roux, N. M. Neary, T. J. Halsey, C. J. Small, A. M. Martinez-Isla, M. A. Ghatei, N. A. Theodorou and S. R. Bloom

Department of Metabolic Medicine (C.W.l.R., N.M.N., C.J.S., M.A.G., S.R.B.), Imperial College, and Department of Surgery (T.J.H., A.M.M.-I., N.A.T.), Hammersmith Hospital Trust, London W12 ONN, United Kingdom

Address all correspondence and requests for reprints to: Professor S. R. Bloom, Department of Metabolic Medicine, Imperial College, London W12 ONN, United Kingdom. E-mail: s.bloom{at}imperial.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Patients with gastric or esophageal surgery and transection of the vagus nerve may suffer from appetite and weight loss but without dysphagia or mechanical obstruction to eating. The gastric hormone ghrelin stimulates food intake and GH release in rodents and man. However, rodents with vagotomy are not sensitive to the feeding effects of ghrelin.

Objective: The objective of the study was to determine whether humans with vagotomy are sensitive to ghrelin.

Study Design: The design was a double-blind, randomized, placebo-controlled trial.

Setting: This was a hospital-based study.

Patients: Six men and one woman who all had a previous complete truncal vagotomy with lower esophageal or gastric surgery entered and completed the study.

Intervention: Each patient received 120-min infusions of saline, 1 pmol/kg·min ghrelin, and 5 pmol/kg·min ghrelin on 3 separate days. After 90 min, a buffet meal was served.

Main Outcome Measure: Energy intake at the buffet meal was measured.

Results: Ghrelin-stimulated GH release in a dose-dependent manner was measured, confirming bioactivity. However, no change in energy intake was observed with either dose of ghrelin [energy intake (kilojoules): saline 2805 ± 812; ghrelin 1 pmol/kg·min, 2486 ± 767; ghrelin 5 pmol/kg·min, 2382 ± 543; P = not significant].

Conclusions: Ghrelin is unlikely to be an effective appetite-stimulatory treatment for patients with vagotomy and esophageal or gastric surgery. Our results suggest that an intact vagus nerve may be required for exogenous ghrelin to increase appetite and food intake in man.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PATIENTS WHO HAVE had gastric or esophageal surgery with transection of the vagus nerve frequently suffer from loss of appetite and loss of weight (1). In a series of patients who had Ivor Lewis esophagogastrectomy, 60% lost weight, whereas only 40% suffered from dysphagia (1). This disparity suggests that mechanical obstruction alone may not fully explain the weight loss seen after such surgery.

A better understanding of the mechanism underlying this weight loss would allow development of more effective treatments. Ghrelin, the endogenous ligand for the GH secretagogue (GHS) receptor, is a 28-amino-acid peptide produced primarily in the stomach (2). After gastrectomy, plasma ghrelin levels were reported to be decreased by at least 50% (3).

Peripheral ghrelin administration leads to increases in food intake and GH release in rodents (4, 5) and humans (6). Circulating plasma ghrelin levels increase before a meal and decrease after the consumption of nutrients (7). Therefore, ghrelin has been postulated to increase appetite and act as a meal initiator (7). Ghrelin may also play a role in body weight regulation because plasma ghrelin decreases with weight gain and increases with weight loss (8).

Evidence that ghrelin stimulates motor activity in the gastrointestinal tract is mounting. Ghrelin may affect gastrointestinal motility via specific ghrelin receptors located on myenteric, vagal, and central neurons (9). Ghrelin also modulates the cardiovascular system. Injection of ghrelin was reported to decrease mean arterial pressure without a significant change in heart rate and increase the cardiac index and stroke volume index (10).

Transection of the vagus nerve has been reported to abolish the orexigenic effect of ghrelin in rodents (11, 12). In the latter study, the postghrelin GH response in vagotomized rodents remained present but was attenuated. Recently it has been reported that patients who have had a vagotomy retain their GH response to exogenous ghrelin, although appetite was not assessed (13).

We previously reported that ghrelin stimulates energy intake in cancer patients with appetite loss (14). However, patients with gastric surgery or vagotomy were excluded. The effect of ghrelin on food intake in patients with vagotomy remained to be determined.

The aim of the current study was to compare appetite and food intake in patients who had undergone vagotomy after either saline or ghrelin infusion.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Experimental subjects

All studies were performed according to the principles of the Declaration of Helsinki and approved by our local research and ethics committee (reference no. 2002/6316). Written informed consent was obtained from all subjects. Exclusion criteria included pregnancy, chronic medical illness likely to interfere with the study and surgery, or radiotherapy or chemotherapy within the past month.

Nine men and one woman were recruited. Three patients were excluded before the commencement of the study due to significant comorbidity. The remaining seven patients (six men and one woman) entered and completed the study (Table 1Go). All patients had undergone transection of anterior and posterior trunks of the vagus nerve and removal of the fundus of the stomach for proven or suspected malignancy. Patients 1–3 underwent total gastrectomy. The anatomy of the vagotomy was similar in all cases and all were operated on by a single surgeon. The mean time between surgery and infusions was 13 ± 6 months (mean ± SEM). The mean age was 63 ± 4 yr and mean body mass index (BMI) 22.2 ± 1.5 kg/m2.


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  		TABLE 1. Details of patients with vagotomy

 
Methods

Human ghrelin was purchased from Peninsula Laboratories (St. Helens, Merseyside, UK) and 0.9% saline from Bayer (Haywards Heath, UK). The limulus amoebocyte lysate assay test for pyrogen was negative and the peptide was sterile on culture. Fasted subjects had two iv cannulae placed at 0900 h, one for infusion and the other for blood sampling. The infusions of ghrelin or saline were started at 1000 h (t = 0 min). Each subject received infusion of saline, 1 pmol/kg·min ghrelin, or 5 pmol/kg·min ghrelin on three separate days at least 48 h apart in a double-blind, randomized, cross-over design. The infusion rates were chosen from previous studies. Ghrelin (5 pmol/kg·min) has been reported to increase energy intake in healthy volunteers (6) and cancer patients with their vagus nerve intact (14). However, patients with gastrectomy and associated reduction in endogenous ghrelin (3) might have enhanced sensitivity to exogenous ghrelin. Hence, a lower rate of 1 pmol/kg·min was also included. Subjects received infusions for 120 min. After infusion for 90 min, lunch was served, comprising preweighed pasta lunch presented in excess and water. Subjects were told to eat until they were comfortably full. All subjects finished eating within 20 min. The remaining food was weighed after the meal and energy intake calculated. Venous blood was collected at –60, 0, 60, 90, 120, and 150 min. Plasma was separated after centrifugation and stored immediately at –20 C. Patients were asked to complete visual analog scales (VASs) (possible scores 0–100 mm) rating hunger, sickness, and satiety at baseline (t = 0), before lunch (t = 90), and after lunch (t = 150). Positions on these scales were measured by a blinded observer. Pulse and blood pressure were measured every 30 min.

Hormone assays

All samples were assayed simultaneously and in duplicate to eliminate the effect of interassay variation. Ghrelin-like immunoreactivity was measured with a specific and sensitive RIA. The assay measures both octanoyl and des octanoyl ghrelin and does not cross-react with any known gastrointestinal or pancreatic peptide hormones. The antisera (SC-10368) was obtained from Santa Cruz Biotechnology (Santa Cruz, CA) and used at a final dilution of 1:50,000. The 125I ghrelin was prepared using Bolton & Hunter reagent (Amersham International, Aylesbury, UK) and purified by reverse phase-HPLC using a linear gradient from 10 to 40% acetonitrile, 0.05% trifluoroacetic acid over 90 min. The specific activity of ghrelin label was 48 Bq/fmol. Then 25 and 100 µl of unextracted plasma was assayed. The assay was performed in a total volume of 0.7 ml of 0.06 M phosphate buffer (pH 7.2), containing 0.3% BSA, and incubated for 3 d at 4 C before separation of free and antibody-bound ghrelin by charcoal adsorption. The assay detected changes of 25 pmol/liter of plasma ghrelin with a 95% confidence limit, with an intraassay coefficient of variation of 5.5%. Plasma peptide YY (PYY) and glucagon-like peptide-1-(7–36)-amide (GLP-1) concentrations were quantified using established in-house RIAs and antibodies (15, 16).

GH was measured by Advantage automated chemiluminescent immunoassay (Nichols Institute Diagnostics, San Clemente, CA).

Statistical analysis

Results are expressed as means ± SEM. Energy intake and plasma ghrelin and GH levels were compared using a paired t test. VASs were analyzed using a Wilcoxon signed rank test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
No adverse events were observed or reported on any infusion day

Fasting baseline ghrelin levels were similar on all infusion days [ghrelin picomoles per liter: saline day 295 ± 55, ghrelin 1 pmol/kg·min day 284 ± 50, ghrelin 5 pmol/kg·min day 326 ± 57 pmol/liter; P = not significant (NS)]. On the saline control day, there was no significant change in plasma ghrelin after the meal [ghrelin picomoles per liter: 90 min (premeal), 271 ± 70; 150 min (60 min postmeal), 236 ± 48; P = 0.25].

Plasma ghrelin was significantly elevated by ghrelin infusion at 1 pmol/kg·min and increased further by ghrelin infusion at 5 pmol/kg·min (plasma ghrelin picomoles per liter at 90 min: saline day 270 ± 70, ghrelin 1 pmol/kg·min day 958 ± 60, ghrelin 5 pmol/kg·min day 4087 ± 253; P < 0.05). A significant and dose-dependent rise in GH was associated with ghrelin infusion, confirming that the ghrelin was biologically active (GH milliinternational units per liter at 90 min: saline, 1.2 ± 0.5; ghrelin 1 pmol/kg·min, 32.6 ± 6.2; ghrelin 5 pmol/kg·min, 60.9 ± 12.7; P < 0.005) (Fig. 1Go). Plasma PYY and GLP-1 concentrations were similar during saline and ghrelin infusions [PYY (picomoles per liter) at 90 min: saline, 22.6 ± 3.5; ghrelin 1 pmol/kg·min, 23.3 ± 3.5; ghrelin 5 pmol/kg·min, 23.7 ± 5.5; GLP-1 (picomoles per liter) at 90 min: saline, 53.0 ± 9.0; ghrelin 1 pmol/kg·min, 54.9 ± 10.5; ghrelin 5 pmol/kg·min, 57.7 ± 14.1].



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  		FIG. 1. GH response immediately before lunch (t = 90 min) after infusion of 0.9% saline, 1 pmol/kg·min ghrelin, and 5 pmol/kg·min ghrelin. *, P < 0.05.

 
There were no statistically significant differences in energy intake among the three infusion days (Fig. 2Go) [energy intake (kilojoules): saline, 2805 ± 812; ghrelin 1 pmol/kg·min, 2486 ± 767; ghrelin 5 pmol/kg·min, 2382 ± 543; P = NS; percentage change from saline infusion day: ghrelin 1 pmol/kg·min, –4 ± 11%; ghrelin 5 pmol/kg·min, –5 ± 8%]. These findings are in marked contrast with the 31% increase in energy intake reported in cancer patients without vagotomy.



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  		FIG. 2. A, Buffet meal energy intake after infusions of 0.9% saline, 1 pmol/kg·min ghrelin, and 5 pmol/kg·min ghrelin. Results are presented as percent energy intake of saline day. B, Energy intake (millijoules) for individual patients. Each line represents one patient. Mean energy intake is presented as a bold line.

 
Analysis of the VAS revealed no significant differences in hunger or sickness ratings among the three infusion days [hunger score at 90 min (millimeters): saline, 70 ± 9; ghrelin 1 pmol/kg·min, 62 ± 9; ghrelin 5 pmol/kg·min, 61 ± 10; sickness score at 90 min (millimeters) saline, 6.0 ± 1.4; ghrelin 1 pmol/kg·min, 6.0 ± 1.5; ghrelin 5 pmol/kg·min, 5.8 ± 1.5]. Although there were no differences in how full they felt before the meal between infusions, patients reported feeling less full after the meal on the 5 pmol/kg·min ghrelin infusion day, compared with saline [satiety score (millimeters) at 150 min: saline, 65 ± 10; ghrelin 5 pmol/kg·min, 56 ± 11; P < 0.05]. There was no difference in the meal appreciation score after the meal [meal appreciation score (millimeters): saline, 68 ± 9, ghrelin 1 pmol/kg·min, 71 ± 8, ghrelin 5 pmol/kg·min, 68 ± 8; P = NS for ghrelin 1 pmol/kg·min and ghrelin 5 pmol/kg·min vs. saline].

Analysis of the pulse recordings revealed a reduction in pulse rate with 5 pmol/kg·min ghrelin but not at the lower dose of 1 pmol/kg·min. [difference in pulse rate at 90 min from baseline (beats/min): saline, 0.6 ± 2.0; ghrelin 1 pmol/kg·min, 0.4 ± 1.2; ghrelin 5 pmol/kg·min, –5.6 ± 1.4; P = 0.01 for ghrelin 5 pmol/kg·min vs. saline]. There were no significant differences in systolic blood pressures between infusion days. However, a significant reduction in diastolic blood pressure was observed with the higher dose ghrelin infusion, compared with saline [difference in diastolic blood pressure at 90 min from baseline (millimeters of mercury): saline, 4.2 ± 2.6; ghrelin 1 pmol/kg·min, –1.1 ± 2.0; ghrelin 5 pmol/kg·min, –6.8 ± 2.2; P < 0.001 for ghrelin 5 pmol/kg·min vs. saline].


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The observation that ghrelin no longer stimulated food intake in rodents after vagotomy was initially surprising, but, to date, this had not been studied in man. We have observed that iv ghrelin did not alter appetite or energy intake in patients with vagotomy and partial or total gastrectomy. However, we found, as with vagotomized rodents (12), that the GH-stimulatory response after ghrelin administration was present. Ghrelin was also associated with small but statistically significant reductions in pulse rate and mean blood pressure, the latter as previously reported by Nagaya et al. (10). There were no differences in the hunger, fullness, or sickness scores during ghrelin infusion. There was, however, a significant reduction in the postprandial fullness score after ghrelin (5 pmol/kg·min) infusion. In addition to its effects on appetite and GH release, ghrelin has been reported to stimulate gastric motility (17). The reduction in postprandial satiety observed in the current study might be explained by an alteration in gastric motility associated with ghrelin infusion. Thus, ghrelin stimulated GH release and may have stimulated gastric motility but did not alter appetite or energy intake. These findings are in marked contrast with the 31% increase in energy intake in similarly aged cancer patients with intact vagus nerves (14) and to the 28% increase in energy intake observed in healthy volunteers (6).

Similar to our findings, exogenous ghrelin has been shown not to stimulate food intake in vagotomized rodents, although the GH response was present. These findings were attributed to the absence of effective ghrelin receptors that are normally present in the afferent vagus (12). Vagotomy may affect hypothalamic neuronal activation normally seen after peripheral ghrelin administration. In rats that had undergone vagotomy, reduced expression of c-fos, a marker of early neuronal activation, was observed in neuropeptide Y and GHRH neurons after peripheral ghrelin administration, compared with sham-operated controls (12). These changes in hypothalamic activation to ghrelin could be explained by the lack of afferent vagal responses. Alternatively, it could be that vagotomy is itself associated with alterations in hypothalamic neuronal circuitry. Further work is needed to elucidate the role of the ghrelin GHS receptor of the vagus nerve.

Patients with total or partial gastrectomies have decreased plasma ghrelin levels despite a low BMI (18). The fundus of the stomach is the single largest source of ghrelin and in its absence the other ghrelin producing tissues do not have the capacity to compensate fully (3, 18). It might have been hypothesized that reduced plasma ghrelin concentrations would lead to up-regulation of ghrelin receptors and that iv ghrelin would be associated with an enhanced appetite response. The rise in plasma GH associated with ghrelin infusion in the current study was similar to that seen at similar rates of ghrelin infusion in previous studies (6, 14). Thus, the GH response to ghrelin in patients with vagotomy appeared to remain intact. This provides evidence of activity at the GHS ghrelin receptor. The disparity in the absence of a feeding but presence of a GH response in our study could be explained if ghrelin’s feeding effects required an intact vagus nerve, but the GH-releasing effects were signaled by direct action on the hypothalamus.

Patients frequently suffer from profound weight loss after gastric surgery and vagotomy (1). Indeed the absolute energy intake at the buffet meal of this group on the saline infusion day was considerably less than that seen in a previous study of healthy volunteers (6) [energy intake (kilojoules): patient with vagotomy 2805 ± 812 vs. healthy volunteers 4713 ± 344]. It may be that reduction or even absence of a feeding response to endogenous ghrelin in patients with vagotomy contributes to their weight loss. Weight gain could be beneficial to support recovery of postoperative and cachectic patients. From a treatment perspective, our results suggest that ghrelin is unlikely to be an effective appetite-stimulatory treatment for patients who have had esophageal or gastric surgery with vagotomy. From a mechanistic perspective, this study suggests that in humans, as in rodents, an intact vagus nerve may be required for exogenous ghrelin to increase appetite and food intake.


   Acknowledgments
 
We thank Professor Malcolm Alison, Ms. Julia Jones, Dr. Maralyn Druce, and the patients who participated in the trial. We also thank the Medical Research Council and the Wellcome Trust for program grant support.


   Footnotes
 
This work was supported by a program grant support from the Medical Research Council and Wellcome Trust. C.W.l.R. and N.M.N. are Wellcome Clinical Research Training Fellows.

First Published Online May 24, 2005

* C.W.l.R. and N.M.N. contributed equally to this paper.

Abbreviations: BMI, Body mass index; GHS, GH secretagogue; GLP-1, glucagon-like peptide-1-(7–36)-amide; NS, not significant; PYY, plasma peptide YY; VAS, visual analog scale.

Received December 23, 2004.

Accepted May 17, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. King RM, Pairolero PC, Trastek VF, Payne WS, Bernatz PE 1987 Ivor Lewis esophagogastrectomy for carcinoma of the esophagus: early and late functional results. Ann Thorac Surg 44:119–122[Abstract]
  2. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K 1999 Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660[CrossRef][Medline]
  3. Jeon TY, Lee S, Kim HH, Kim YJ, Son HC, Kim DH, Sim MS 2004 Changes in plasma ghrelin concentration immediately after gastrectomy in patients with early gastric cancer. J Clin Endocrinol Metab 89:5392–5396[Abstract/Free Full Text]
  4. Tschop M, Smiley DL, Heiman ML 2000 Ghrelin induces adiposity in rodents. Nature 407:908–913[CrossRef][Medline]
  5. Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA, Batterham RL, Taheri S, Stanley SA, Ghatei MA, Bloom SR 2001 Ghrelin causes hyperphagia and obesity in rats. Diabetes 50:2540–2547[Abstract/Free Full Text]
  6. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR 2001 Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86:5992[Abstract/Free Full Text]
  7. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS 2001 A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50:1714–1719[Abstract/Free Full Text]
  8. Cummings DE, Overduin J, Foster-Schubert KE 2004 Gastric bypass for obesity: mechanisms of weight loss and diabetes resolution. J Clin Endocrinol Metab 89:2608–2615[Free Full Text]
  9. Peeters TL 2003 Central and peripheral mechanisms by which ghrelin regulates gut motility. J Physiol Pharmacol 54(Suppl 4):95–103
  10. Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya H, Hayashi Y, Kangawa K 2001 Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol 280:R1483–R1487
  11. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, Makino S, Fujimiya M, Niijima A, Fujino MA, Kasuga M 2001 Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 120:337–345[CrossRef][Medline]
  12. Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, Kangawa K, Nakazato M 2002 The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 123:1120–1128[CrossRef][Medline]
  13. Takeno R, Okimura Y, Iguchi G, Kishimoto M, Kudo T, Takahashi K, Takahashi Y, Kaji H, Ohno M, Ikuta H, Kuroda Y, Obara T, Hosoda H, Kangawa K, Chihara K 2004 Intravenous administration of ghrelin stimulates growth hormone secretion in vagotomized patients as well as normal subjects. Eur J Endocrinol 151:447–450[Abstract]
  14. Neary NM, Small CJ, Wren AM, Lee JL, Druce MR, Palmieri C, Frost GS, Ghatei MA, Coombes RC, Bloom SR 2004 Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J Clin Endocrinol Metab 89:2832–2836[Abstract/Free Full Text]
  15. Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak JM, Bloom SR 1985 Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 89:1070–1077[Medline]
  16. Kreymann B, Williams G, Ghatei MA, Bloom SR 1987 Glucagon-like peptide-17–36: physiological incretin in man. Lancet 2:1300–1304[Medline]
  17. Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, Hosoda H, Kojima M, Kangawa K 2000 Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 276:905–908[CrossRef][Medline]
  18. Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, Suda M, Koh T, Natsui K, Toyooka S, Shirakami G, Usui T, Shimatsu A, Doi K, Hosoda H, Kojima M, Kangawa K, Nakao K 2001 Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab 86:4753–4758[Abstract/Free Full Text]



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