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Departments of Medicine (J.K., L.J.C., I.M.C., S.L.W.) and Surgery (M.B., A.D., N.L.R.), Columbia University, College of Physicians & Surgeons, New York, New York 10032
Address all correspondence and requests for reprints to: Judith Korner, M.D., Ph.D., Florence Irving Assistant Professor of Clinical Medicine, Columbia University, College of Physicians & Surgeons, 650 West 168th Street, Black Building, Room 905, New York, New York 10032. E-mail: jk181{at}columbia.edu.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The gastrointestinal peptide hormones, ghrelin and peptide YY (PYY), have been shown to modulate metabolism and appetite. Ghrelin is produced primarily by A cells in the oxyntic glands of the stomach fundus. A unique posttranslational acylation with octanoic acid is required for bioactivity (9) and may also be necessary for efficient passage of ghrelin across the blood-brain barrier (10). Although originally described as an inducer of GH release, ghrelin has more recently been implicated in modulating appetite, food intake, and energy expenditure. In the rat, administration of ghrelin stimulates feeding, increases body weight, and decreases fat utilization through stimulation of neurons that express the orexigenic peptides neuropeptide Y and agouti-related protein in the hypothalamus (11, 12); iv injection of ghrelin in humans induces hunger and food intake (13). The high level of ghrelin before a meal and subsequent postprandial fall indicate that ghrelin may play a role in meal initiation in normal weight humans (14). Plasma levels of ghrelin are down-regulated in obese individuals (15, 16), but results are conflicting as to whether food intake further suppresses ghrelin secretion in obese humans (14, 17, 18, 19). Weight loss by caloric restriction is associated with an increase in circulating concentrations of ghrelin (12, 17, 20). Cross-sectional and prospective studies that examine ghrelin concentrations before and after surgically induced weight loss, however, differ with regard to changes in basal levels and meal-related oscillations (8). The effect of RYGBP on the active octanoylated form of ghrelin is unknown.
The secretion of PYY from L cells lining the distal small bowel and colon occurs shortly after food intake, before ingested nutrients arrive in the distal intestine, and subsequently through direct stimulation by nutrients, particularly fat and protein. PYY infusion decreases 24-h food intake in lean and obese humans (21, 22). These effects are mediated presumably through inhibition of gut motility by way of vagal efferent neurons that descend from the hindbrain (23), and via inhibition of neuropeptide Y2 receptors in the hypothalamus, leading to disinhibition of neurons that express the anorectic peptides 
-MSH and cocaine-and-amphetamine-regulated transcript (24). Obese individuals have lower fasting plasma PYY levels compared with normal weight control subjects (22).
We sought to determine whether RYGBP affects fasting and postprandial levels of total and active ghrelin and PYY. Three groups of adult women were studied: lean subjects; patients who lost weight after RYGBP and who were currently weight stable; and subjects who were matched to the RYGBP group for age and BMI. Insulin and leptin concentrations were also quantified. In addition, subjects were asked to complete visual analog scales (VAS) for hunger and satiety to determine whether any differences in appetite between groups were correlated with differences in ghrelin or PYY levels.
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Subjects and Methods |
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Three groups of adult female subjects were studied and consisted of the following: group 1, lean controls defined as those with a BMI (weight in kilograms divided by the square of the height in meters) from 18–25 kg/m2 (n = 8); group 2, individuals who had undergone RYGBP at least 1 yr before evaluation (n = 12); and group 3, individuals with no history of bariatric surgery who were BMI- and age-matched to subjects in group 2 (n = 12). Although the study was open to both genders, only females volunteered for the postsurgical study, necessitating enrollment of only female controls, particularly because leptin and possibly ghrelin concentrations vary according to gender (25, 26). All subjects were weight stable, defined as weight change of less than 5% over the 3-month period preceding the study. Control subjects were excluded from the study if they had a history of diabetes; uncontrolled hypertension; current or recent tobacco use; use of prescription or over-the-counter weight loss products within the prior 6 months; heart, neurological, or renal disease; depression; eating disorder; use of antipsychotics, neuroleptics, opiates, or oral glucocorticoids; allergy to cocoa products; or lactose intolerance. All subjects signed an informed consent form approved by the Western Institutional Review Board.
The surgical procedure consisted of creation of a 20- to 30-ml pouch that was divided from the proximal lesser curvature of the stomach and excluded the fundus. The pouch was anastomosed to a Roux limb of jejunum created by division of the jejunum 75 cm distal to the ligament of Treitz and anastomosing the afferent biliopancreatic limb to the jejunum 150 cm distally. Division of the vagus nerve and its branches was avoided.
Protocol
Subjects arrived at the Clinical Research Center in the morning after an overnight fast of at least 10 h duration and were weighed in undergarments and a light gown. Subjects consumed a chilled chocolate-flavored test meal (Optifast; Novartis, Minneapolis, MN; 474 ml, 320 kcal, 50% carbohydrate, 35% protein, 15% fat) within a 15-min period. Venous blood was drawn before the meal and 30, 60, 90, 120, and 180 min after meal consumption. Subjects also completed a validated VAS questionnaire at 0 and 180 min (27). The VAS consisted of 100-mm lines with words anchored at each end describing extreme sensations of hunger, satiety, sweet cravings, and nausea or abdominal discomfort. Subjects were asked to make a vertical mark across the line corresponding to their feelings. Quantification was performed by measuring the distance from the left end of the line to the mark.
Hormone measurements
Plasma hormone measurements were performed on blood samples in EDTA tubes that were centrifuged for 15 min at 4 C immediately after collection and stored at –80 C until assayed. Thawed samples were not refrozen for other assay measurements. Due to the number of samples, measurements for each hormone were performed in different assays with the inclusion of controls to determine the interassay variability. Plasma to be used for quantification of octanoyl ghrelin was aliquoted immediately after centrifugation into tubes containing 25 µl 1 N HCl per 0.5 ml plasma. Leptin was measured with a human RIA kit (LINCO Research, Inc., St. Charles, MO) using a 125I-iodinated human leptin tracer. Total plasma immunoreactive ghrelin was measured by a RIA kit (Phoenix Pharmaceuticals, Belmont, CA) using 125I-iodinated ghrelin tracer and a rabbit polyclonal antibody against full-length, octanoylated human ghrelin that recognizes the acylated and des-acyl forms of the hormone. In our laboratory, the lower limit of detection for this assay was 20 pg/ml; the coefficient of variation was 8.5% within assays and 11.3% between assays (28). The bioactive octanoylated form of ghrelin was measured with a RIA kit (LINCO Research) using 125I-labeled ghrelin tracer and guinea pig antighrelin antibody that has less than 0.1% cross-reactivity with des-octanoylghrelin. The lower limit of detection for this assay was 8 pg/ml, with 7% intraassay and 13% interassay coefficients of variation. Plasma levels of PYY were measured after extraction using a commercial RIA kit (Phoenix Pharmaceuticals) containing 125I-labeled human PYY(3–36) and antibody against human PYY(3–36) that exhibits 100% cross-reactivity with full-length PYY. In brief, a Sep-pak C-18 cartridge was equilibrated with 60% acetonitrile in 1% trifluoroacetic acid followed by 1% trifluoroacetic acid in H2O. Plasma was acidified with 1% trifluoroacetic acid and loaded onto the pretreated cartridge. The peptide was eluted with 60% acetonitrile in 1% trifluoroacetic acid, dried, and reconstituted in assay buffer provided with the kit. Plasma stripped of PYY was created by vortexing with Sipernat (silicon dioxide; Degussa Corporation, Teterboro, NJ) followed by centrifugation and extraction with a Sep-pak cartridge, as described above, and was added to the standards to avoid effects of nonspecific assay interference. Recoveries were established by extraction of known amounts of standards from stripped plasma and have been calculated to be a mean of 67%; values were adjusted for the recovery in each assay. Addition of a kallikrein inhibitor as suggested by the manufacturer did not yield significantly different results and was, therefore, omitted. The rest of the procedure was per manufacturer’s protocol. The lower limit of detection was 14 pg/ml, and the coefficients of variation were 11% within and 13% between assays. Plasma insulin was measured with the Immulite Analyzer (Diagnostic Products Corp., Los Angeles, CA) with the lower limit of detection of 2 µIU/ml. Serum glucose was measured by the hexokinase method. Hormone measurements were performed on all subjects, with the exception of octanoylated ghrelin that was not performed on two lean subjects and one BMI-matched control. All samples were assayed in duplicate.
Statistical analysis
Significant differences between groups were determined by one-way ANOVA followed by Fisher’s protected least-difference test. P 
0.05 was considered statistically significant. Insulin resistance (IR) was calculated using the homeostasis model of assessment (HOMA) IR (29, 30). Values for the area under the curve (AUC) were calculated with the use of the trapezoidal rule. Linear regression analysis was used to assess the correlation between BMI and plasma leptin levels. Mean values ± SEM are reported.
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Results |
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Table 1
shows the clinical characteristics of each of the three study groups. There were no significant differences in age, body weight, BMI, or waist circumference between the RYGBP and matched controls. All subjects were weight stable. Subject characteristics before and after RYGB are shown in Table 2. The mean postoperative period was 35 ± 5 months (range, 15–71 months). Despite a mean weight loss of 36%, nine of the 12 postbypass subjects were still obese (BMI 
30 kg/m2), and the remaining three subjects were overweight (BMI > 25 kg/m2).
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Fasting plasma total ghrelin levels were nearly identical between RYGBP (425 ± 54 pg/ml) and the matched controls (424 ± 28 pg/ml), and highest in lean controls (564 ± 103 pg/ml), but this difference was not statistically significant (P = 0.1). The response to the test meal was comparable between lean and RYGBP groups, with 27% and 20% maximal suppression, respectively (Fig. 1). The magnitude of suppression of ghrelin was significantly diminished in the matched controls (17%) compared with the lean group. AUC for the 180-min period was not significantly different between groups.
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). The magnitude of maximal suppression of octanoylated ghrelin was more marked than with total ghrelin, but similar among groups, ranging from 44–47%. AUC of octanoylated ghrelin was lowest in the matched controls but not significantly different from the RYGBP subjects. The ratio of fasting octanoylated to total ghrelin was 37, 35, and 30% in the lean, RYGBP, and matched control groups, respectively. Plasma PYY concentrations
Fasting plasma PYY concentrations tended to be highest in the lean controls (31 ± 7 pg/ml) but not statistically different from RYGBP (19 ± 2 pg/ml) or matched control (22 ± 5 pg/ml) groups. In response to the test meal, there was an early exaggerated rise in PYY levels in the RYGBP group, such that the peak PYY concentration (163 ± 24 pg/ml) was significantly greater compared with matched (58 ± 17; P < 0.01) and lean (77 ± 23; P < 0.05) controls (Fig. 2). AUC at 90 min in the RYGBP group was approximately 2- to 3-fold higher compared with lean and matched controls, respectively (Fig. 2).
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Fasting glucose concentrations were higher in the BMI-matched group (96 ± 2 mg/dl) compared with the RYGBP (91 ± 2; P = 0.1) and lean (89 ± 3; P < 0.05) groups. Fasting insulin concentrations were significantly higher in the matched controls compared with both the lean and RYGBP subjects (Fig. 3). Although the surgical group exhibited exaggerated acute phase insulin secretion, levels rapidly returned to baseline, whereas levels in the matched controls remained elevated for a longer period. HOMA IR indices were nearly identical between lean and RYGBP subjects and significantly higher in the BMI-matched controls (Fig. 3).
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). Leptin concentrations correlated with BMI (r = 0.68; P < 0.001), yet the postoperative subjects tended to be relatively hypoleptinemic (leptin concentration below the regression line) compared with their matched controls (Fig. 4B).
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VAS measurements were used to quantify feelings of hunger, satiety, and nausea or abdominal discomfort pre meal and 3 h post meal (Table 3). No differences were detected in hunger or postmeal abdominal discomfort. A tendency toward greater satiety was reported in the lean (P = 0.1) and RYGBP (P = 0.08) groups compared with the overweight/obese controls, but this result did not reach statistical significance. Ratings of satiety did not correlate with peak PYY values (r = 0.1; P = 0.5). There was less premeal nausea/abdominal discomfort reported in the RYGBP group, and none of these subjects experienced symptoms suggestive of dumping syndrome.
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Discussion |
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The effects of RYGB on ghrelin concentrations are inconsistent among earlier reports (8). Fasting ghrelin concentrations have been shown to decrease further after RYGB, compared with either preoperative levels in prospective studies (31) or with nonsurgical obese controls in cross-sectional studies (17, 19, 32). Meal-related fluctuations of ghrelin levels were either absent (17) or inconsistent (19). In other studies, plasma ghrelin levels were unchanged from preoperative values in patients who were stable at a reduced weight (33, 34). Plasma ghrelin levels have also been observed to increase in patients after RYGB who were experiencing active weight loss (33, 35). In agreement with our results, others have shown that fasting ghrelin levels 12 months after RYGB were similar to nonoperated BMI-matched controls (35). Possible explanations for these varied results include different surgical techniques, such as location of the staple line that partitions the stomach and determines the size of the upper gastric pouch and length of the biliopancreatic limb (8). Surgical resection of the various autonomic fibers that innervate the foregut may also affect both short- and long-term regulation of ghrelin secretion (8, 36).
Levels of the bioactive form of ghrelin that is modified by O-n-octanoylation at the serine 3 residue (9) have not been reported after bariatric surgery. The differences in fasting levels of active ghrelin between both overweight groups and the lean controls are more marked, compared with the differences observed between total ghrelin values. In addition, the magnitude of suppression of octanoylated ghrelin is 60–160% greater than that observed with total ghrelin but is similar among all three groups. It has been suggested that the ratio of octanoyl to des-octanoyl ghrelin may regulate the balance between adipogenesis and lipolysis in response to nutritional status (37). We, therefore, calculated the ratio of active to total ghrelin but found that there were no significant differences between groups.
Obese individuals exhibit lower fasting levels of PYY compared with lean subjects (22, 38). The effects of weight loss on plasma PYY levels have been less extensively studied. After vertical banded gastroplasty fasting PYY concentrations are increased after 12 months, however, this study failed to show an increase in PYY concentrations in lean, obese, and postoperative subjects within 60 min of ingestion of a 475-kcal semiliquid test meal (38). PYY concentrations are also higher in fasted subjects after jejunoileal bypass, compared with nonoperative obese subjects, but remain the same within 60 min after a 280-kcal test meal (39). We show that there is a remarkable early postprandial spike in PYY concentrations in RYGBP subjects. The mechanism of this early exaggerated response is unclear but may be due to bypassing the stomach—and specifically the pylorus—that would be expected to increase the rate at which food enters the small bowel. It is possible that the several-fold increase in postprandial PYY concentrations may contribute to an early sense of satiety and the ability of an individual to reduce meal size. However, results from the VAS questionnaire only showed a tendency that did not reach statistical significance for the surgery subjects to report increased satiety compared with their matched controls. There was also no clear correlation between peak PYY values and measures of satiety by VAS. Due to the large interindividual variability of VAS responses, a study of more subjects, particularly at shorter postprandial periods, may be necessary to demonstrate statistically significant differences in satiety. Of note, our assay measured total PYY concentrations and did not differentiate between the two circulating forms, PYY(1–36) and PYY(3–36). It is possible, that these different forms and their sites of action exert different physiological effects. For example, central administration of PYY(1–36) is actually a potent orexigen (40), whereas systemic injection has an emetic effect (41). Discrepant results of both the peripheral and central effects of PYY(3–36) on food intake and body weight in rodents have been reported (42). To date, however, the only studies in humans show that peripheral administration of PYY(3–36) decreases food intake (21, 22). Administration of PYY(1–36) in humans has, to our knowledge, not been reported.
After RYGBP, there is marked improvement in insulin sensitivity (33, 44, 45). Although one report shows that fasting insulin concentrations are reduced to levels similar to those of nonoperated obese women matched for BMI (35), our results show that insulin concentrations in the RYGBP are significantly lower than BMI-matched controls and are indistinguishable from lean subjects. This difference may be due to the shorter postoperative period in the former study. Another study shows blunted first-phase insulin secretion after a meal in subjects who underwent RYGBP and laparoscopic adjustable silicone gastric banding; however, the first postmeal blood draw was at 60 min (19), and in fact, there is an exaggerated early insulin response at 30 min demonstrated in this study. Despite this exaggerated insulin response, none of our subjects reported symptoms suggestive of dumping syndrome.
Interestingly, leptin levels in the RYGBP group are comparable with lean controls and not the BMI-matched group. This relative hypoleptinemia has also been observed in female subjects after diet-induced weight loss whose leptin levels per unit of fat mass were compared with body composition-matched females studied at their normal weight (46). It is possible that diet or surgically induced weight loss in females, resets a leptin "thermostat" or threshold to that of greater leptin sensitivity. Although administration of leptin to obese individuals is of limited efficacy (47), replacing leptin in patients who have regained leptin sensitivity may be a strategy to prevent counter-regulatory signals from pushing the metabolic machinery toward promotion of weight regain (43, 48).
In conclusion, the results in this study suggest that weight maintenance after RYGBP may be due, in part, to earlier and increased satiety induced not just by volume restriction but also by an early and exaggerated PYY response to nutrients. In addition, fasting ghrelin levels do not increase to the extent reported with diet-induced weight loss; octanoylated ghrelin is actually significantly lower than lean controls. Such changes in ghrelin secretion may contribute to a paradoxical decrease in hunger, despite calorie restriction and weight reduction, compared with individuals who lose weight via diet alone. After bypass, there is also amelioration of the insulin resistance associated with obesity. It is clear that a weight-reduced individual is not the hormonal or metabolic equivalent of an individual who is naturally at the same weight. It is not yet clear whether some of these differences are attributable to calorie restriction, weight loss, and/or the bypass procedure itself. It will be important to decipher the regulation of these changes so that pharmaceuticals could be developed that might induce some of the physiological effects of gastric bypass surgery.
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Acknowledgments |
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Footnotes |
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First Published Online October 13, 2004
Abbreviations: AUC, Area under the curve; BMI, body mass index; HOMA, homeostasis model of assessment; IR, insulin resistance; PYY, peptide YY; RYGBP, Roux-en-Y gastric bypass; VAS, visual analog scale(s).
Received June 7, 2004.
Accepted September 9, 2004.
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), RYGBP (•), and BMI-matched (
) groups.