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Keywords:

  • bariatric surgery;
  • leptin;
  • growth hormone;
  • IGF-1;
  • appetite

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Objective: Ghrelin is an enteric peptide with strong orexigenic and adipogenic effects. Plasma ghrelin levels are decreased in obese subjects but increase after weight loss; this increase is not observed after Roux-en-Y gastric bypass (RYGB). Prospective and comparative data after adjustable silicone gastric banding (ASGB) have not been reported previously.

Research Methods and Procedures: Overnight fasting plasma ghrelin concentration was measured in morbidly obese subjects at baseline and 3, 6, 12, and 24 months after ASGB (n = 8) or RYGB (n = 5) and in nonoperated controls (n = 7).

Results: After RYGB, body weight (BW) decreased by 29.5 ± 5.5 kg (mean ± SE, p < 0.001), whereas plasma ghrelin failed to increase significantly (+167 ± 119 pg/mL, not significant). In contrast, after ASGB, BW decreased less (by 22.8 ± 5.9 kg; p < 0.001), and plasma ghrelin significantly increased by 377 ± 201 pg/mL (p = 0.025). Neither BW nor plasma ghrelin changed in nonoperated controls. Plasma leptin decreased in both operated groups (similarly p < 0.05) but not in nonoperated controls. Plasma growth hormone and insulin-like growth factor 1 were not correlated with changes in plasma ghrelin concentrations.

Discussion: Plasma ghrelin levels failed to increase during substantial weight loss after RYGB, but did increase in response to lesser weight loss after ASGB. These findings suggest that the plasma ghrelin response after weight loss is impaired after exclusion of major parts of the stomach and the duodenum (RYGB), and the smaller long-term weight loss after ASGB compared with RYGB may be due, at least in part, to an absent increase in plasma ghrelin after RYGB.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Obesity is emerging worldwide as a leading cause of morbidity and mortality, despite all preventive and therapeutic attempts. Surgical procedures are increasingly performed as an effective method of treatment. In recent years, the interest in circulating mediators in the homoeostasis of appetite and of body weight (BW)1 has increased.

Ghrelin is a recently discovered 28-amino acid peptide that was first described as a potent endogenous ligand of the growth hormone (GH) secretagogue receptor (1). The primary source of ghrelin is the stomach, but it is also produced in the intestines, kidneys, pituitary, hypothalamus, and placenta (2, 3, 4). In addition to its GH-stimulating effect, ghrelin is strongly orexigenic and adipogenic (5, 6), showing a rise before and a fall shortly after every meal, suggesting a possible role in the induction of a meal (7, 8). Ghrelin levels are negatively correlated with BW (9, 10, 11, 12). In obese subjects, the typical decline of plasma ghrelin after a meal is not seen (13), and weight loss results in an increase in plasma ghrelin concentration (14); these effects contribute to the difficulty of obese subjects to achieve and maintain weight loss.

Surgical gastric restriction procedures are effective methods for achieving weight loss in morbidly obese subjects (15). Roux-en-Y gastric bypass (RYGB) and adjustable silicone gastric banding (ASGB) are currently performed most frequently. In RYGB, the stomach is divided into an upper small pouch and a larger lower segment carrying an anastomosis with Roux-en-Y intestinal configuration to the proximal gastric pouch, resulting in the intended gastric bypass. In ASGB, a hollow silicone band is placed around the upper stomach, forming a small proximal gastric pouch. In a recent study, patients undergoing gastric bypass surgery did not show an increase in plasma ghrelin concentrations (14), possibly contributing to the greater weight loss as compared with conventional methods. Prospective data comparing subjects after RYGB and ASGB have not been reported previously.

Research Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Subjects

After institutional review board approval, twenty patients with morbid obesity (BMI > 37 kg/m2) undergoing bariatric surgery gave written, informed consent to participate. In five subjects, the treatment was gastric bypass [proximal Roux-en-Y anastomosis (RYGB); open procedure, Roux limb 75 cm], and in eight, the treatment was a laparoscopically placed ASGB (Swedish gastric banding; Obtech Medical AG, Baar, Switzerland). Seven obese subjects who did not receive operations served as controls. Before surgical intervention, all patients were interviewed and examined by a physician, a psychologist, and a nutritionist. All patients were followed by the Division of Endocrinology, Diabetology, and Clinical Nutrition at 3, 6, 12, and 24 months after surgery.

Hormone Measurements

At each visit, plasma samples were collected in the fasting state, processed within 30 minutes, and frozen at −70 °C. Ghrelin was measured using a radioimmunoassay with 125-I-labeled bioactive ghrelin as the tracer and a rabbit polyclonal antibody (Phoenix Pharmaceuticals Inc., Belmont, CA). Leptin was measured by a commercial radioimmunoassay kit using 125-I-labeled leptin and rabbit anti-human leptin serum (Linco Research Inc., St. Charles, MO).

Statistical Analyses

All data are expressed as means ± SE. Spearman correlation tests, unpaired Student's t tests (two-sided), and Mann-Whitney U tests were used for comparison of single time points among groups, depending on whether the data showed a normal distribution. Repeated-measures ANOVA was performed for serial measurements (Statistica 6.0 for Windows; StatSoft Inc., Tulsa, OK). When multiple comparisons were made among groups, a correction according to Bonferroni was applied.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

There were no significant differences among the groups with regard to age, BMI, and plasma levels of ghrelin, leptin, GH, and insulin-like growth factor 1 (IGF-1) at baseline (Mann-Whitney U test). Both RYGB and ASGB resulted in distinct weight loss (Table 1, Figure 1, p < 0.01) during the follow-up period of 2 years. The weight loss was more pronounced after RYGB compared with ASGB in the first 6 months. In control subjects, BMI did not change (−0.3 ± 0.4 kg/m2), and plasma ghrelin concentrations remained unchanged (Table 1; +22.5 ± 50.6 pg/mL, not significant), whereas after gastric banding, a significant increase (+377.3 ± 201.4 pg/mL, p < 0.05; +64.6 ± 15.6%) was observed. After gastric bypass, the change of plasma ghrelin was not statistically significant (167.6 ± 119.7 pg/mL; +54.7 ± 40.6%), and the trend to higher ghrelin levels was driven by only one patient who showed a distinct increase in ghrelin concentration (+632 pg/mL). Changes in ghrelin levels were negatively correlated with the change of BW in all patients (p < 0.009, Figure 2) and in the subgroup of ASGB patients (p = 0.04).

Table 1.  Age, BMI, and plasma hormone concentrations at baseline and 24 months after treatment
 Controls (N = 7) (5 women, 2 men)ASGB (N = 8) (6 women, 2 men)RYGB (N = 5) (5 women)
 024 months024 months024 months
  • Data are means ± SE. All parameters at baseline were not significantly different between groups.

  • *

    p < 0.001, vs controls.

  • p < 0.05, vs controls.

Age (years)49.9 ± 2.6 41.1 ± 2.6 43.8 ± 4.4 
BMI (kg/m2)41.1 ± 1.041.0 ± 1.441.7 ± 1.033.2 ± 1.7*43.6 ± 2.032.9 ± 3.0*
Plasma ghrelin (pg/mL)553.0 ± 105.0554.2 ± 112.4461.5 ± 187.7838.9 ± 387.3240.4 ± 47.4408.0 ± 147.8
Plasma leptin (ng/mL)34.9 ± 8.437.2 ± 10.028.2 ± 2.317.7 ± 2.838.0 ± 4.121.8 ± 4.1
Plasma growth hormone (μg/L)0.39 ± 0.270.64 ± 0.290.13 ± 0.060.49 ± 0.270.08 ± 0.032.04 ± 0.67
Plasma IGF-1 (nM)13.2 ± 1.015.8 ± 1.915.4 ± 1.819.2 ± 2.711.9 ± 2.716.5 ± 2.3
image

Figure 1. Changes of BW from baseline during 24 months in the three groups of patients. The decrease of BW at 3 and 6 months in the RYGB group was larger than in the ASGB group. *, p < 0.05; **, p < 0.01; ***, p < 0.001 vs. controls. #, p < 0.05; ##, p < 0.01 vs. ASGB.

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image

Figure 2. Correlation between changes of BMI and changes of plasma ghrelin after 24 months in the three treatment groups. The correlation of changes in plasma ghrelin with those of BMI after 24 months were also significant in the subgroup of ASGB (p = 0.024), but not in the RYGB group.

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After bariatric surgery, leptin levels decreased significantly (Table 1; RYGB −16.2 ± 6.4 ng/mL, p < 0.004; ASGB −10.4 ± 2.4 ng/mL, p < 0.05). Change in plasma leptin was highly correlated with change in BMI (Figure 3; p < 0.001). Plasma GH and IGF-1 did not change significantly in either treated group (Table 1).

image

Figure 3. Correlation between changes of BMI and changes of plasma leptin after 24 months in three treatment groups.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Ghrelin appears to play an important role in both initiation of a meal and the long-term regulation of BW (7, 8, 9). The increase in plasma ghrelin shortly before and the decrease after a meal are well documented in lean subjects (7), the pattern in obese patients still remaining controversial (13, 14). In a recent report, a smaller or absent increase in plasma ghrelin concentration after RYGB, depending on energy balance, was demonstrated (16). Cummings et al. described an absent increase in ghrelin concentrations in obese patients after gastric bypass surgery and a loss of the normal diurnal pattern when compared with obese subjects who did not receive surgery and with nonobese control subjects (14). The authors suggested that suppression of ghrelin might, at least in part, be responsible for the weight-reducing effect of gastric bypass surgery; however, these data were not obtained prospectively, and data in weight-losing subjects treated with other surgical procedures were not reported. Recent publications have corroborated the findings of decreased ghrelin levels after RYGB (16, 17, 18) and low levels compared with obese control subjects (18).

The present prospective study compared concentrations of plasma ghrelin in obese subjects treated with and without different gastric restriction procedures, and measurements were started before surgical treatment. Because fasting ghrelin levels correlate with the 24-hour profile (area under the curve) (7), plasma ghrelin concentrations were measured in the morning after overnight fasting.

During the follow-up period of 24 months after surgical intervention, the observed loss of BW in the two treated groups was comparable with previous observations. Generally, a loss of 50% to 80% of excess BW can be achieved by RYGB, compared with a somewhat smaller loss (30% to 50%) after ASBG (15). Plasma ghrelin increased in the present study after gastric banding surgery, but not after gastric bypass.

The data of the present study demonstrate that weight loss alone does not predict plasma ghrelin concentrations. Because of its orexigenic effect, the higher concentrations of ghrelin after ASGB may contribute, at least in part, to the smaller weight loss after purely restrictive bariatric operations than after RYGB (17, 18, 19). RYGB results in a varying degree of malabsorption; however, this does not result in malnutrition (17). Therefore, deficiency of certain micronutrients may develop (15).

The difference in ghrelin concentrations may be an explanation of why appetite is reduced after RYGB (21, 22, 23) despite weight loss, which usually causes compensatory hyperphagia. The mechanism of how gastric bypass leads to permanent lowering of ghrelin despite weight loss is unclear. In the short term, an empty stomach is associated with increased ghrelin levels; a permanent absence of food in the stomach and duodenum (as a result of RYGB) may lead to this long-lasting suppression.

As expected, the changes of plasma leptin after treatment were strongly correlated with the changes of BMI, both showing a continuous decrease after surgery. The difference between the changes of plasma leptin and ghrelin when BW decreased after the two interventions further supports the assumption that the specific surgical technique, and not weight loss alone, determined plasma ghrelin concentrations.

Plasma concentrations of human GH and IGF-1 as markers of human GH action remained unchanged in all groups, indicating that the observed changes of plasma ghrelin as a strong GH secretagogue receptor activator did not influence secretion or action of GH in the long run. These findings argue against a critical physiological role for ghrelin in normal GH regulation.

In summary, the present study demonstrates that in patients with morbid obesity undergoing bariatric surgery, significant increases in plasma ghrelin concentrations after ASGB are observed in contrast to patients with RYGB. The data, therefore, suggest a ghrelin-lowering effect of surgical procedures that exclude major parts of the stomach, the duodenum, and upper parts of the jejunum from contact with ingested nutrients. The higher levels with ASGB, as compared with RYGB, may contribute to the smaller weight loss of patients undergoing ASGB.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

There was no outside funding/support for this study. We thank Merih Guglielmetti for her assistance in the statistical analysis and Vreny Wyss, Käthy Dembinsky, and Susy Vosmeer for technical assistance.

Footnotes
  • 1

    Nonstandard abbreviations: BW, body weight; GH, growth hormone; RYGB, Roux-en-Y gastric bypass; ASGB, adjustable silicone gastric banding; IGF-1, insulin-like growth factor 1.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References