Brief Article Open Access
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Aug 14, 2012; 18(30): 4044-4050
Published online Aug 14, 2012. doi: 10.3748/wjg.v18.i30.4044
Effects of vagus nerve preservation and vagotomy on peptide YY and body weight after subtotal gastrectomy
Hyung Hun Kim, Moo In Park, Sang Ho Lee, Hyun Yong Hwang, Sung Eun Kim, Seun Ja Park, Won Moon
Hyung Hun Kim, Moo In Park, Sung Eun Kim, Seun Ja Park, Won Moon, Departments of Internal Medicine, Kosin University College of Medicine, Busan 602-702, South Korea
Sang Ho Lee, Departments of Surgery, Kosin University College of Medicine, Busan 602-702, South Korea
Hyun Yong Hwang, Departments of Laboratory Medicine, Kosin University College of Medicine, Busan 602-702, South Korea
Author contributions: Kim HH performed statistical analysis and wrote this paper as the first author; Park MI designed this study and reviewed this paper as a corresponding author; Lee SH performed operation in all patients enrolled in this study; Hwang HY was responsible for measuring hormones and other laboratory values; and Kim SE, Park SJ and Moon W supported the analysis of results and discussion.
Correspondence to: Moo In Park, MD, Department of Internal Medicine, Kosin University College of Medicine, 34 Amnam-dong, Seo-gu, Busan 602-702, South Korea. mipark@ns.kosinmed
Telephone: +82-51-9905205 Fax: +82-51-9905055
Received: January 15, 2012
Revised: March 15, 2012
Accepted: April 9, 2012
Published online: August 14, 2012

Abstract

AIM: To investigate the relationship between the function of vagus nerve and peptide YY3-36 and ghrelin levels after subtotal gastrectomy.

METHODS: We enrolled a total of 16 patients who underwent subtotal gastrectomy due to gastric cancer. All surgeries were performed by a single skilled surgeon. We measured peptide YY3-36, ghrelin, leptin, insulin, growth hormone levels, and body weight immediately before and one month after surgery.

RESULTS: Vagus nerve preservation group showed less body weight loss and less increase of peptide YY3-36 compared with vagotomy group (-5.56 ± 2.24 kg vs -7.85 ± 1.57 kg, P = 0.037 and 0.06 ± 0.08 ng/mL vs 0.19 ± 0.12 ng/mL, P = 0.021, respectively). Moreover, patients with body weight loss of less than 10% exhibited reduced elevation of peptide YY3-36 level, typically less than 20% [6 (66.7%) vs 0 (0.0%), P = 0.011, odd ratio = 3.333, 95% confidence interval (1.293, 8.591)].

CONCLUSION: Vagus nerve preservation contributes to the maintenance of body weight after gastrectomy, and this phenomenon may be related to the suppressed activity of peptide YY3-36.

Key Words: Anal cushion, Anal incontinence, Liquids continence test, Wexner score, Hemorrhoidectomy



INTRODUCTION

Body weight loss is a common and serious outcome in patients with gastric cancer who are treated by gastrectomy[1]. Weight loss is correlated with declines in postoperative quality of life and is the most reliable indicator of malnutrition, which impairs immune function, infection susceptibility, and survival[2,3]. Postoperative body weight loss can be explained by mechanisms such as reduced food intake, appetite loss caused by the reduced reservoir or delayed gastric emptying[4,5], diarrhea[6] and malabsorption. Malabsorption, in turn, is linked to reduced secretion of gastric acid[7] and pancreatic insufficiency[8,9]. In addition, it was recently suggested that alterations of endocrine status, such as reduced gastrin[8] or ghrelin[10], and increased cholecystokinin levels[5,8] might be involved in weight loss after gastrectomy. However, the mechanism of body weight loss after gastrectomy has not been fully clarified.

The 28-amino acid peptide ghrelin is the endogenous ligand for the growth hormone secretagogue receptor 1a, which stimulates the release of growth hormone from the pituitary gland[11]. The majority of ghrelin is produced by X/A-like endocrine cells of the gastric oxyntic mucosa, and smaller amounts are secreted by other organs, such as the intestine, pancreas, kidney and hypothalamus[12,13]. Ghrelin has a number of physiologic effects that result in positive energy balance, such as promoting the appetite signal in the hypothalamus as an antagonist to leptin[14], stimulating gastrointestinal activities such as peristalsis, gastric acid secretion, and pancreatic excretion through the vagal nerves[15], and regulation of fat metabolism. Peptide YY3-36, a 36 amino acid gut-derived hormone, reduces food intake over the short term in animals[16,17] and in humans[18] by stimulating hypothalamic neuropeptide Y receptors. Preprandial decreases and postprandial increases in plasma peptide YY3-36 concentrations suggest that peptide YY3-36 is one of satiety signals. Peptide YY3-36 is suggested to be involved in intermediate term inhibition of food intake, in contrast to the classical short term regulators such as cholecystokinin[16]. Dose-dependent reductions in food intake following peripheral peptide YY3-36 administration are observed in both fasting and freely feeding rodents[16,17,19,20]. In healthy human volunteers, intravenous infusion of peptide YY3-36 caused a sustained decrease in appetite and food intake for more than 24 h[18]. Moreover, gastric bypass results in a more robust peptide YY3-36 response to caloric intake, which, in conjunction with decreased ghrelin levels, may contribute to the sustained efficacy of this procedure[21]. One animal study suggested that peptide YY release is inhibited through a vagal cholinergic mechanism due to significant elevations of basal and food-induced release of peptide YY after truncal vagotomy[22].

Recently, one study reported that reductions in visceral fat were significantly lower in patients in whom the vagus nerve was preserved than in patients who had undergone vagotomy, and concluded that the vagus nerve locally regulates amounts of intra-abdominal fat tissue[23]. However, they did not mention the hormonal changes regarding the effect of vagotomy and vagus nerve preservation on body weight loss. Therefore, we aimed to reveal the correlation between the effect of vagus nerve preservation and vagotomy on peptide YY3-36 or ghrelin levels after subtotal gastrectomy in relation to body weight loss.

MATERIALS AND METHODS
Patients

Sixteen patients who underwent subtotal gastrectomy at Gospel Hospital, Kosin University College of Medicine, Busan, South Korea between January 2008 and January 2010 were enrolled in the study. The inclusion criteria were as follows: (1) adenocarcinoma of the stomach confirmed by histopathologic examination; (2) preoperative clinical staging of less than stage IIIA (International Union Against Cancer tumor, node, metastasis stage classification); (3) curative surgical treatment (R0) (i.e., subtotal gastrectomy with D1 or D2 lymph node dissection); and (4) age between 20 and 80 years. The exclusion criteria were the presence of any of the following: (1) cardiopulmonary, liver, or renal dysfunction; (2) active dual malignancy; (3) pregnancy; (4) past history of gastrointestinal surgery; and (5) postoperative complications after subtotal gastrectomy that could affect oral food intake, such as anastomotic leakage, pancreatitis, and mechanical ileus. Sixteen patients were randomized by sealed-envelope selection and divided into two study groups. The random allocation sequence was concealed until interventions were assigned. Nine patients were treated by subtotal gastrectomy with vagus nerve preservation (vagus nerve preservation group), and seven patients underwent both subtotal gastrectomy and vagotomy (vagotomy group). The study was approved by the Kosin University Ethics Committee, and all patients provided written informed consent before study entry in accordance with the Declaration of Helsinki.

Operative procedures

In seven cases, subtotal gastrectomy and bilateral truncal vagotomy were performed with D1 or D2 lymph node dissection followed by Billroth-I or Roux-en-Y reconstruction. The hepatic and celiac branches of the vagus nerve were preserved in nine patients who underwent Billroth-I or Roux-en-Y reconstruction after subtotal gastrectomy with D1 or D2 lymph node dissection. The greater omentum was largely preserved in all cases. All operations were performed by a surgeon with a history of over 1000 gastric cancer operations over the course of 20 years. An ultrasonic knife (Ultracision®, Ethicon Endo Surgery, Cincinnati, OH, United States) was used to prevent nerve damage in the vagus nerve preservation group. Electrical impulses were produced by a high-frequency ultrasound generator, transferred to a hand piece and converted into mechanical movement at a frequency of 55.5 kHz. This instrument was chosen because of the relatively low temperatures generated, ranging from 50 °C to 100 °C, which limit damage to adjacent tissue compared to conventional diathermy. Diathermy produces temperatures up to 400 °C, resulting in char formation and deleterious thermal effects to a distance of up to 1 cm from the blade, as well as the extensive formation of necrotic tissue.

Body weight and blood sampling for hormone measurement in the fasted state

Peptide YY3-36, ghrelin, leptin, insulin, and growth hormone levels as well as body weights were measured 1 d before surgery (day 1) and 1 mo after surgery (day 30). Venous fasting blood samples were taken early in the morning on day 1 and day 30 for the measurement of plasma concentrations of the following hormones: peptide YY3-36 (enzyme-linked immunosorbent assay, Phoenix Pharmaceuticals Inc., Belmont, CA, United States), total ghrelin (radioimmunoassay, Linco Research Inc., St. Louis, MO, United States), leptin (radioimmunoassay, Linco Research Inc.), insulin (two-site sandwich immunoassay, Siemens Medical Solutions Diagnostics, Los Angeles, CA, United States), and human growth hormone (radioimmunometric assay, Packard Instruments Inc., Chicago, IL, United States). Peptide YY3-36, insulin, and growth hormone levels were measured with the V-MAX 220 VAC enzyme-linked immunosorbent assay reader (Molecular Devices, Sunnyvale, CA, United States), ADVIA Centaur XP (Siemens, Tarry-town, NY, United States), and COBRA II Gamma counter (PacKard, Waltham, MA, United States), respectively. Ghrelin and leptin were analyzed with the COBRA II Gamma Counter (PacKard, United States). Total protein, albumin, total cholesterol, and triglyceride levels were tested with the ADVIA 2400 (Siemens, Tarry-town, NY, United States).

Statistical analysis

Statistical analysis was performed using the SPSS software (version 16.0, SPSS, Chicago, IL, United States). Differences between the vagus nerve preservation group and the vagotomy group, including sex, age, stages of gastric cancer, body weight, body mass index (BMI), and laboratory values were assessed by Fisher’s exact tests and Mann-Whitney U test. Wilcoxon signed rank test was used to calculate the changes between pre and post-operative values in body weight, BMI, peptide YY3-36, ghrelin, leptin, insulin, growth hormone, and other laboratory profiles of all patients. The differences in body weight, BMI, hormones, and other laboratory values between two groups one month after operation were calculated by Mann-Whitney U test. Fisher’s exact tests were used to validate the correlation among vagus nerve preservation, body weight loss of less than 10%, and peptide YY3-36 level increases of less than 20 %. Statistical significance was set at a P value of < 0.05.

RESULTS
Patient characteristics

The study flow diagram is summarized in Figure 1. There was no significant difference in age, sex, body weight, BMI, clinical stage of gastric cancer, pathologic types, and laboratory profiles including hormone values between the two groups. Table 1 summarizes the clinical and laboratory background of the 16 patients who completed the study.

Table 1 Baseline characteristics of patients in two groups.
Operative procedureVagus nerve preservation (n = 9)Vagotomy (n = 7)P
Age (yr)59.01 ± 13.1252.74 ± 6.40NS
Sex (male/female)6/34/3NS
Body weight (kg)62.01 ± 11.2263.13 ± 6.01NS
BMI (kg/m2)23.21 ± 2.4024.41 ± 3.53NS
TNM stageNS
II5 (55.5)3 (42.8)
IIIa4 (45.5)4 (57.2)
Pathologic typeNS
Differentiated6 (66.6)4 (57.2)
Undifferentiated3 (33.4)3 (42.8)
ReconstructionNS
Billroth-15 (55.5)5 (71.4)
Roux-en-Y4 (45.5)2 (28.6)
Laboratory values
Peptide YY3-36 (ng/mL)0.38 ± 0.100.42 ± 0.07NS
Ghrelin (pg/mL)693.71 ± 211.25703.90 ± 238.89NS
Leptin (ng/mL)3.88 ± 4.595.50 ± 7.99NS
Insulin (mIU/L)6.36 ± 3.956.47 ± 4.66NS
Growth hormone (ng/mL)1.51 ± 2.341.4 ± 0.18NS
HOMA index1.70 ± 1.241.68 ± 1.38NS
Albumin (g/dL)3.71 ± 0.433.63 ± 0.52NS
Total protein (g/dL)6.93 ± 0.506.92 ± 1.04NS
Total cholesterol (mg/dL)204.91 ± 25.23209.63 ± 21.11NS
Triglyceride (mg/dL)171.72 ± 49.21140.41 ± 45.24NS
Figure 1
Figure 1 Flowchart for investigating effects of vagus nerve preservation and vagotomy on body weight and hormones such as peptide YY, ghrelin, leptin, insulin and growth hormone after total gastrectomy due to gastric cancer. AGC: Advanced gastric cancer; POD: Postoperative day; STG: Subtotal gastrectomy.
Changes of body weight and hormones

All patients demonstrated body weight loss (preoperative body weight: 62.51 ± 9.02 kg vs postoperative body weight: 56.02 ± 8.32 kg, P < 0.001) with decreased BMI (23.71 ± 2.94 kg/m2vs 21.33 ± 2.62 kg/m2, P < 0.001). All patients have increased peptide YY3-36 (0.41 ± 0.09 ng/mL vs 0.52 ± 0.15 ng/mL, P = 0.020), and decreased ghrelin (787.34 ± 421.33 pg/mL vs 506.21 ± 201.10 pg/mL, P = 0.007) postoperatively. Insulin levels were significantly increased in most patients (4.59 ± 6.12 mIU/L vs 1.86 ± 1.49 mIU/L, P = 0.001). There was no correlation between the basal values of peptide YY3-36 and the extent of body weight loss. There were no significant changes in leptin and growth hormone levels after surgery. No significant differences were found in albumin, protein, triglyceride, and total cholesterol levels either. Vagus never preservation group showed less decrease in body weight (-5.56 ± 2.24 kg vs -7.85 ± 1.57 kg, P = 0.037) and BMI (-1.91 ± 1.04 kg/m2vs -2.91 ± 0.39 kg/m2, P = 0.031) than vagotomy group. Moreover, less elevation of peptide YY3-36 was observed in vagus nerve preservation group (0.06 ± 0.08 ng/mL vs 0.19 ± 0.12 ng/mL, P = 0.021) than vagotomy group. Total protein, albumin, total cholesterol, and triglyceride levels did not show significant changes between two groups after surgery. These results were presented in Table 2. Vagus never preservation group showed significantly lower post-operative peptide YY3-36 value than vagus nerve preserved group (0.44 ± 0.07 ng/mL vs 0.62 ± 0.17 ng/mL, P = 0.020). However, there were no differences in other post-operative values between two groups. These post-operative findings were described in Table 2.

Table 2 Changes of body weight, body mass index and laboratory values between pre-operation and one month after operation and parameters at 1 mo after operation in two groups.
Changes from pre-operation to one month after operation
One month after operation
Operative procedureVagus nerve preservation (n = 9)Vagotomy (n = 7)PVagus nerve preservation (n = 9)Vagotomy (n = 7)P
Body weight (kg)-5.56 ± 2.24-7.85 ± 1.570.037156.44 ± 10.4055.29 ± 4.99NS
BMI (kg/m2)-1.91 ± 1.04-2.91 ± 0.390.031221.21 ± 2.0821.44 ± 3.39NS
Peptide YY3-36 (ng/mL)0.06 ± 0.080.19 ± 0.120.02130.44 ± 0.070.62 ± 0.170.0204
Ghrelin (pg/mL)-229.23 ± 196.69-174.47 ± 174.58NS464.47 ± 235.49529.43 ± 134.86NS
Leptin (ng/mL)-2.08 ± 3.38-3.56 ± 7.41NS1.79 ± 1.311.94 ± 1.79NS
Insulin (mIU/L)9.5 ± 12.3711.01 ± 8.26NS15.86 ± 10.8917.48 ± 7.48NS
HOMA index0.33 ± 0.150.35 ± 0.43NS2.10 ± 1.792.25 ± 1.99NS
Growth hormone (ng/mL)0.07 ± 3.320.19 ± 0.12NS1.58 ± 2.201.95 ± 2.44NS
Albumin (g/dL)-0.05 ± 0.32-0.14 ± 0.66NS3.64 ± 0.313.50 ± 0.43NS
Total protein (g/dL)-0.17 ± 0.71-0.18 ± 0.83NS6.77 ± 0.416.78 ± 0.88NS
Total cholesterol (mg/dL)-4.00 ± 15.21-6.57 ± 10.42NS200.88 ± 22.31203.00 ± 27.82NS
Triglyceride (mg/dL)-14.33 ± 20.40-11.71 ± 18.93NS157.44 ± 38.29128.71 ± 36.66NS
Relationships among vagus nerve preservation, body weight change, and peptide YY3-36 change

Patients were separated into groups based on the changes of body weight and peptide YY3-36. Body weight loss of less than 10% was more frequently observed in vagus nerve preservation group [6 (66.7%) vs 0 (0.0%), P = 0.011, odd ratio (OR) = 3.333, 95% confidence interval (95% CI) (1.293, 8.591); Figure 2A]. Increases of peptide YY3-36 less than 20% was more frequently noticed in the vagus nerve preservation group after surgery [5 (55.6%) vs 0 (0.0%), P = 0.034, OR = 2.750, 95% CI (1.258, 6.010); Figure 2B]. Patients with body weight loss of less than 10% exhibited significant correlation with reduced elevation of peptide YY3-36 level, typically less than 20% [5 (83.3%) vs 0 (0.0%), P = 0.001, OR = 11.000, 95% CI (1.697, 71.282); Figure 2C].

Figure 2
Figure 2 Correlations among vagus nerve preservation, body weight loss and peptide YY3-36 increase. A: Vagus nerve preservation was correlated with body weight loss less than 10% [66.7% vs 0.0%, P = 0.011, odd ratio (OR) = 3.333, 95% confidence interval (95% CI) (1.293, 8.591)]; B: The vagus nerve preservation group showed significant correlation with peptide YY3-36 level increases of less than 20% [55.6% vs 0.0%, P = 0.034, OR = 2.750, 95% CI (1.258, 6.010)]; C: Patients with body weight loss of less than 10% exhibited tight correlation with reduced elevation of peptide YY3-36 level, typically less than 20% [83.3% vs 0.0%, P = 0.001, OR = 11.000, 95% CI (1.697, 71.282)]. PYY: Peptide YY.
DISCUSSION

Weight loss is a common complication after gastrectomy. However, the effects of different surgical procedures associated with gastrectomy on postoperative body weight loss and hormonal changes are not well understood. In the present study, we examined changes in body weight, peptide YY3-36, ghrelin, leptin, growth hormone, and insulin levels in vagus nerve preservation and vagotomy groups.

Although all 16 patients who underwent subtotal gastrectomy exhibited body weight loss, the vagus nerve preservation group demonstrated significantly less decreases in body weight and BMI than the vagotomy group. This study reproduces the findings of Melissas et al[7] who postulated that this phenomenon might be explained by the energy saving function of the vagus nerve as a major parasympathetic nerve innervating visceral organs. The sympathetic nervous system predominates during energy-spending catabolic states, whereas in energy-saving anabolic states the parasympathetic nervous system prevails[24,25]. Anatomical and physiological studies have demonstrated the innervation of adipose tissue by sympathetic nerves, which in turn accelerate lypolysis of adipocytes[26,27]. The vagotomy group showed significantly greater visceral fat mass reduction than the vagus nerve preservation group[7]. In our study, vagus nerve preservation presented 3.333 fold more chance than vagotomy group for body weight loss less than 10% (95% CI from 1.293 to 8.591).

All patients in this study showed increased peptide YY3-36 levels after subtotal gastrectomy. A previous study demonstrated that stomach gastrin inhibited peptide YY secretion in rats[28]. All study patients lost the antrum after subtotal gastrectomy, therefore reducing the effect of stomach gastrin on peptide YY. This is a possible explanation for the elevation of peptide YY levels in these patients. An alternative explanation for this phenomenon is that there is a negative correlation between fasting peptide YY3-36 and markers of adiposity[18,29-31]. In addition, fasting peptide YY levels are significantly higher in anorexia nervosa sufferers than normal weight controls. In rodent studies, mice exposed to a high-fat diet develop obesity and a concomitant reduction in circulating peptide YY[32,33].

Vagus nerve preservation group demonstrated significantly less increase in peptide YY3-36 than vagotomy group in the present study. Moreover, the vagus nerve preservation group demonstrated a tight correlation with increases in peptide YY3-36 levels of less than 20%. According to a previous animal study, truncal vagotomy resulted in significant elevations of basal and food-induced release of peptide YY[22]. This suggests that peptide YY release is inhibited tonically, probably through a vagal cholinergic mechanism. Adrenergic pathways did not participate in food-stimulated peptide YY release. However, electrical stimulation of the splanchnic nerves increased basal levels of peptide YY, suggesting that the sympathetic nervous system affects the release of peptide YY[22]. This agrees with our finding that the vagus nerve preservation group showed reduced elevation of peptide YY3-36 levels in comparison to the vagotomy group, although increased peptide YY3-36 levels were observed in both groups. An alternative explanation for more elevation of peptide YY3-36 in the vagotomy group could be a compensatory increase in peptide YY3-36 secretion in response to reduced peptide YY3-36 signaling to the hindbrain via the vagus. Thus peptide YY3-36 may exert its effects on body weight by acting centrally, via vagal stimulation, or both. Many lines of evidence suggest that peptide YY3-36 exerts its effects on feeding via the hypothalamus; intra-arcuate injection of peptide YY3-36 reduces feeding, whereas Y2-antagonist injection has the opposite effect[34]. Thus, vagotomy, transection of hindbrain-hypothalamic pathways, can cause compensatory increase of peripheral peptide YY3-36.

When correlations between body weight loss and increase of peptide YY3-36 levels were performed, patients who demonstrated body weight loss of less than 10% exhibited lower increases in peptide YY3-36 levels, less than 20%. Because vagus nerve preservation is associated with lower increases in peptide YY3-36 levels and reductions in body weight loss, it is not clear whether the lower increase in peptide YY3-36 levels actually caused less body weight loss. However, we cannot exclude the possibility that peptide YY3-36 levels influence body weight, as peptide YY3-36 has been shown to suppress appetite and promote weight loss[16,17,19,20,35]. In healthy human volunteers, intravenous infusion of peptide YY3-36 causes sustained decreases in appetite and food intake for more than 24 h[18]. Energy intake by obese subjects during a buffet lunch was reduced by 30% after intravenous infusion of peptide YY3-36[18]. Chronic administration of peptide YY3-36 inhibits food intake and reduced body weight gain in mice, rabbits, and rhesus macaques[16,35,36]. In addition, daily food intake, body weight, and body fat are increased in peptide YY knockout mice in comparison to wild-type mice[32]. Although the number of patients enrolled in the present study was limited, these findings suggest that elevated basal peptide YY3-36 levels may contribute to body weight loss after subtotal gastrectomy.

All patients in this present study demonstrated increased plasma insulin after operation. A previous study showed the partial gastrectomy and intestinal resection induced impaired oral glucose tolerance despite normal insulin concentrations[37]. Increased basal level insulin might reflect the impaired insulin tolerance in the present study although it was not proved by oral glucose tolerance test.

There are five limitations in our study. First, patient appetite was not assessed. Assessing subjects’ appetite on a visual analogue scale before and after surgery would have allowed us to evaluate the relationship between changes in peptide YY3-36 levels and changes in appetite. Second, unfortunately, this present study did not include data from meal-stimulated secretions of peptide YY or other hormones such as glucagon like peptide-1, which could have shed more light on the true interaction effects between vagus nerve preservation/vagotomy and gastrointestinal hormonal functions and body weight. Third, we did not evaluate body composition. Evaluating changes in body composition may have helped to elucidate the correlations between vagus nerve preservation, changes in peptide YY3-36 levels, and changes in specific body composition, especially visceral fat levels. Fourth, only total ghrelin was measured, since active octanoylated ghrelin is unstable. Although both total and active ghrelin appear to be regulated in a similar and parallel manner, future studies will need to focus on measurement of the biologically active form. Finally, small number of patients was enrolled in the present study.

In summary, body weight loss, increased peptide YY3-36 levels, and decreased ghrelin levels were observed in all patients after subtotal gastrectomy. Vagus nerve preservation group showed less decrease in body weight and BMI than vagotomy group. Less increase of peptide YY3-36 was observed in vagus nerve preservation group. Moreover, patients with body weight loss of less than 10% exhibited reduced elevation of peptide YY3-36 level, typically less than 20%. Based on these results and those of previous studies, we concluded that vagus nerve preservation resulted in reduced body weight loss after subtotal gastrectomy, in direct relation with peptide YY3-36 activities and suggest that vagus nerve should be preserved for preventing excessive body weight loss after subtotal gastrectomy due to gastric cancer.

COMMENTS
Background

Body weight loss is a common and serious outcome in patients with gastric cancer who are treated by gastrectomy. Weight loss is correlated with declines in postoperative quality of life and is the most reliable indicator of malnutrition, which impairs immune function, infection susceptibility, and survival. Patients who underwent vagus nerve-preserving procedures lose less body weight than patients treated with vagotomy after gastrectomy.

Research frontiers

Ghrelin has a number of physiologic effects that result in positive energy balance, such as promoting the appetite signal in the hypothalamus as an antagonist to leptin. Peptide YY3-36 is suggested to be involved in intermediate term inhibition of food intake, in contrast to the classical short term regulators such as cholecystokinin. Recently, one study reported that reductions in visceral fat were significantly lower in patients in whom the vagus nerve was preserved than in patients who had undergone vagotomy, and concluded that the vagus nerve locally regulates amounts of intra-abdominal fat tissue.

Innovations and breakthroughs

This study is the first to evaluate relationship between the differences in weight loss between patients treated with vagus nerve-preserving procedures and vagotomy and the changes of peptide YY3-36 and ghrelin levels after subtotal gastrectomy. Vagus nerve preservation group showed less decrease in body weight and BMI than vagotomy group. Less increase of peptide YY3-36 was observed in vagus nerve preservation group. Moreover, patients with body weight loss of less than 10% exhibited reduced elevation of peptide YY3-36 level, typically less than 20%. Based on these results, the authors concluded that vagus nerve preservation resulted in reduced body weight loss after subtotal gastrectomy, in direct relation with peptide YY3-36 activities

Applications

Present study showed that vagus nerve preservation resulted in less decrease in body weight and BMI than vagotomy group. Furthermore, this study suggested plausible peptide YY3-36 activities in this phenomenon. Considering these findings, the authors cautiously suggest to preserve vagus nerve during subtotal gastrectomy for less body weight loss.

Peer review

This is a good experiment study in which authors analyze the cause of the differences in weight loss between patients treated with vagus nerve-preserving procedures and vagotomy in the view of the changes of peptide YY3-36 and ghrelin levels after subtotal gastrectomy. The findings that vagus nerve preservation resulted in reduced body weight loss after subtotal gastrectomy, in direct relation with peptide YY3-36 activities suggesting the possible role of peptide YY3-36 in this phenomenon.

Footnotes

Peer reviewers: Beata Jolanta Jablońska, MD, PhD, Department of Digestive Tract Surgery, University Hospital of Medical University of Silesia, Medyków 14 St., 40-752 Katowice, Poland; Akio Inui, MD, PhD, Professor, Department of Behavioral Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan

S- Editor Lv S L- Editor A E- Editor Xiong L

References
1.  Demas GE, Drazen DL, Nelson RJ. Reductions in total body fat decrease humoral immunity. Proc Biol Sci. 2003;270:905-911.  [PubMed]  [DOI]
2.  Lee SE, Lee JH, Ryu KW, Nam B, Kim CG, Park SR, Kook MC, Kim YW. Changing pattern of postoperative body weight and its association with recurrence and survival after curative resection for gastric cancer. Hepatogastroenterology. 2012;59: 430-435.  [PubMed]  [DOI]
3.  Marinho LA, Rettori O, Vieira-Matos AN. Body weight loss as an indicator of breast cancer recurrence. Acta Oncol. 2001;40:832-837.  [PubMed]  [DOI]
4.  Braga M, Zuliani W, Foppa L, Di Carlo V, Cristallo M. Food intake and nutritional status after total gastrectomy: results of a nutritional follow-up. Br J Surg. 1988;75:477-480.  [PubMed]  [DOI]
5.  Bergh C, Sjostedt S, Hellers G, Zandian M, Sodersten P. Meal size, satiety and cholecystokinin in gastrectomized humans. Physiol Behav. 2003;78:143-147.  [PubMed]  [DOI]
6.  Armbrecht U, Lundell L, Stockbruegger RW. Nutrient malassimilation after total gastrectomy and possible intervention. Digestion. 1987;37 Suppl 1:56-60.  [PubMed]  [DOI]
7.  Melissas J, Kampitakis E, Schoretsanitis G, Mouzas J, Kouroumalis E, Tsiftsis DD. Does reduction in gastric acid secretion in bariatric surgery increase diet-induced thermogenesis? Obes Surg. 2002;12:399-403.  [PubMed]  [DOI]
8.  Friess H, Böhm J, Müller MW, Glasbrenner B, Riepl RL, Malfertheiner P, Büchler MW. Maldigestion after total gastrectomy is associated with pancreatic insufficiency. Am J Gastroenterol. 1996;91:341-347.  [PubMed]  [DOI]
9.  Bae JM, Park JW, Yang HK, Kim JP. Nutritional status of gastric cancer patients after total gastrectomy. World J Surg. 1998;22:254-260; discussion 260-251.  [PubMed]  [DOI]
10.  Takachi K, Doki Y, Ishikawa O, Miyashiro I, Sasaki Y, Ohigashi H, Murata K, Nakajima H, Hosoda H, Kangawa K. Postoperative ghrelin levels and delayed recovery from body weight loss after distal or total gastrectomy. J Surg Res. 2006;130:1-7.  [PubMed]  [DOI]
11.  Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656-660.  [PubMed]  [DOI]
12.  Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology. 2000;141:4255-4261.  [PubMed]  [DOI]
13.  Leite-Moreira AF, Soares JB. Physiological, pathological and potential therapeutic roles of ghrelin. Drug Discov Today. 2007;12:276-288.  [PubMed]  [DOI]
14.  Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K, Hayashi T, Inoue G, Hosoda K, Kojima M. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes. 2001;50:227-232.  [PubMed]  [DOI]
15.  Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, Hosoda H, Kojima M, Kangawa K. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun. 2000;276:905-908.  [PubMed]  [DOI]
16.  Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature. 2002;418:650-654.  [PubMed]  [DOI]
17.  Challis BG, Pinnock SB, Coll AP, Carter RN, Dickson SL, O'Rahilly S. Acute effects of PYY3-36 on food intake and hypothalamic neuropeptide expression in the mouse. Biochem Biophys Res Commun. 2003;311:915-919.  [PubMed]  [DOI]
18.  Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA, Bloom SR. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med. 2003;349:941-948.  [PubMed]  [DOI]
19.  Koda S, Date Y, Murakami N, Shimbara T, Hanada T, Toshinai K, Niijima A, Furuya M, Inomata N, Osuye K. The role of the vagal nerve in peripheral PYY3-36-induced feeding reduction in rats. Endocrinology. 2005;146:2369-2375.  [PubMed]  [DOI]
20.  Halatchev IG, Ellacott KL, Fan W, Cone RD. Peptide YY3-36 inhibits food intake in mice through a melanocortin-4 receptor-independent mechanism. Endocrinology. 2004;145:2585-2590.  [PubMed]  [DOI]
21.  Chan JL, Mun EC, Stoyneva V, Mantzoros CS, Goldfine AB. Peptide YY levels are elevated after gastric bypass surgery. Obesity (Silver Spring). 2006;14:194-198.  [PubMed]  [DOI]
22.  Zhang T, Uchida T, Gomez G, Lluis F, Thompson JC, Greeley GH Jr. Neural regulation of peptide YY secretion. Regul Pept. 1993;48:321-328.  [PubMed]  [DOI]
23.  Miyato H, Kitayama J, Hidemura A, Ishigami H, Kaisaki S, Nagawa H. Vagus nerve preservation selectively restores visceral fat volume in patients with early gastric cancer who underwent gastrectomy. J Surg Res. 2010;173:60-67.  [PubMed]  [DOI]
24.  Niijima ANervous regulation of metabolism. Prog Neurobiol. 1989;33:135-147.  [PubMed]  [DOI]
25.  Scheurink AJ, Steffens AB. Central and peripheral control of sympathoadrenal activity and energy metabolism in rats. Physiol Behav. 1990;909-920.  [PubMed]  [DOI]
26.  Penicaud L, Cousin B, Leloup C, Lorsignol A, Casteilla L. The autonomic nervous system, adipose tissue plasticity, and energy balance. Nutrition. 2000;16:903-908.  [PubMed]  [DOI]
27.  Bamshad M, Aoki VT, Adkison MG, Warren WS, Bartness TJ. Central nervous system origins of the sympathetic nervous system outflow to white adipose tissue. Am J Physiol. 1998;275:R291-R299.  [PubMed]  [DOI]
28.  Gomez G, Englander EW, Greeley GH. Nutrient inhibition of ghrelin secretion in the fasted rat. Regul Pept. 2004;117:33-36.  [PubMed]  [DOI]
29.  Alvarez Bartolome M, Borque M, Martinez-Sarmiento J, Aparicio E, Hernandez C, Cabrerizo L, Fernandez-Represa JA. Peptide YY secretion in morbidly obese patients before and after vertical banded gastroplasty. Obes Surg. 2002;12:324-327.  [PubMed]  [DOI]
30.  Roth JD, Coffey T, Jodka CM, Maier H, Athanacio JR, Mack CM, Weyer C, Parkes DG. Combination therapy with amylin and peptide YY[3-36] in obese rodents: anorexigenic synergy and weight loss additivity. Endocrinology. 2007;148:6054-6061.  [PubMed]  [DOI]
31.  Siahanidou T, Mandyla H, Vounatsou M, Anagnostakis D, Papassotiriou I, Chrousos GP. Circulating peptide YY concentrations are higher in preterm than full-term infants and correlate negatively with body weight and positively with serum ghrelin concentrations. Clin Chem. 2005;51:2131-2137.  [PubMed]  [DOI]
32.  Batterham RL, Heffron H, Kapoor S, Chivers JE, Chandarana K, Herzog H, Le Roux CW, Thomas EL, Bell JD, Withers DJ. Critical role for peptide YY in protein-mediated satiation and body-weight regulation. Cell Metab. 2006;4:223-233.  [PubMed]  [DOI]
33.  Yang N, Wang C, Xu M, Mao L, Liu L, Sun X. Interaction of dietary composition and PYY gene expression in diet-induced obesity in rats. J Huazhong Univ Sci Technolog Med Sci. 2005;25:243-246.  [PubMed]  [DOI]
34.  Abbott CR, Small CJ, Kennedy AR, Neary NM, Sajedi A, Ghatei MA, Bloom SR. Blockade of the neuropeptide Y Y2 receptor with the specific antagonist BIIE0246 attenuates the effect of endogenous and exogenous peptide YY(3-36) on food intake. Brain Res. 2005;1043:139-144.  [PubMed]  [DOI]
35.  Sileno AP, Brandt GC, Spann BM, Quay SC. Lower mean weight after 14 days intravenous administration peptide YY3-36 (PYY3-36) in rabbits. Int J Obes (Lond). 2006;30:68-72.  [PubMed]  [DOI]
36.  Koegler FH, Enriori PJ, Billes SK, Takahashi DL, Martin MS, Clark RL, Evans AE, Grove KL, Cameron JL, Cowley MA. Peptide YY(3-36) inhibits morning, but not evening, food intake and decreases body weight in rhesus macaques. Diabetes. 2005;54:3198-3204.  [PubMed]  [DOI]
37.  Wapnick S, Jones JJ. Changes in glucose tolerance and serum insulin following partial gastrectomy and intestinal resection. Gut. 1972;13:871-873.  [PubMed]  [DOI]