ORIGINAL ARTICLES
Gut Hormone Profiles Following Bariatric Surgery Favor an
Anorectic State, Facilitate Weight Loss, and Improve
Metabolic Parameters
Carel W. le Roux, MRCP,* Simon J. B. Aylwin, MRCP, PhD,† Rachel L. Batterham, MRCP, PhD,‡
Cynthia M. Borg, MRCS,§ Frances Coyle, MRCP,† Vyas Prasad, MRCS,* Sandra Shurey, MSc,储
Mohammad A. Ghatei, PhD,* Ameet G. Patel, FRCS,§ and Stephen R. Bloom, FRCP, DSc*
Objective: To study the effect of bariatric surgery on the enterohypothalamic endocrine axis of humans and rodents.
Background: Bariatric surgery is the most effective obesity treatment as it achieves substantial and sustained weight loss. Glycemic
control and enhanced satiation improve before substantial weight
loss occurs. Gut peptides, acting both peripherally and centrally,
contribute to glycemic control and regulate food intake.
Methods: We examined meal-stimulated responses of insulin, ghrelin, peptide YY (PYY), glucagon-like-peptide-1 (GLP-1), and
pancreatic polypeptide (PP) in humans and rodents following different bariatric surgical techniques.
Results: Compared with lean and obese controls, patients following
Roux-en-Y gastric bypass (RYGB) had increased postprandial
plasma PYY and GLP-1 favoring enhanced satiety. Furthermore,
RYGB patients had early and exaggerated insulin responses, potentially mediating improved glycemic control. None of these effects
were observed in patients losing equivalent weight through gastric
banding. Leptin, ghrelin, and PP were similar in both the surgical
groups. Using a rodent model of jejuno-intestinal bypass (JIB), we
showed elevated PYY and GLP-1 in JIB rats compared with shamoperated rats. Moreover, exogenous PYY reduced food intake and
blockade of endogenous PYY increased food intake. Thus, higher
plasma PYY following JIB may contribute to reduced food intake
and contribute to weight loss.
Conclusions: Following RYGB and JIB, a pleiotropic endocrine
response may contribute to the improved glycemic control, appetite
reduction, and long-term changes in body weight.
(Ann Surg 2006;243: 108 –114)
From the *Department of Metabolic Medicine, Hammersmith Hospital,
Imperial College London, U.K.; ‡Centre for Diabetes and Endocrinology, Department of Medicine, Rayne Institute, University College London, U.K.; Departments of †Endocrinology and §Surgery, King’s College Hospital, London, U.K.; and 㛳Department of Surgical Research,
Northwick Park Hospital, London, U.K.
Reprints: Stephen R. Bloom, FRCP, DSc, Department of Metabolic Medicine, Hammersmith Hospital, Du Cane Road, Imperial College London,
U.K. E-mail: s.bloom@imperial.ac.uk.
Copyright © 2005 by Lippincott Williams & Wilkins
ISSN: 0003-4932/06/24301-0108
DOI: 10.1097/01.sla.0000183349.16877.84
108
T
he rising prevalence of obesity in developed societies is
causing a major health threat in terms of morbidity and
mortality.1 The complications of obesity, especially type 2
diabetes mellitus (T2DM), are placing growing demand on
healthcare resources.1,2 Existing medical therapeutic strategies to achieve and maintain clinically significant weight loss
remain limited.3 Surgical procedures for the treatment of
obesity are, however, highly effective in achieving substantial
and sustained weight loss,4,5 but they are technically demanding and costly and carry small but significant rates of morbidity and mortality.6
Dramatic improvements in glycemic control have been
observed in subjects with T2DM following bariatric surgery,
and specifically the Roux-en-Y gastric bypass (RYGB) procedure.7–11 In the early postoperative period following
RYGB, many patients with T2DM discontinue all antidiabetic medication, and may achieve normal fasting plasma
glucose concentrations even before substantial weight loss
has occurred.10,11 It has been postulated that the improvements in glycemic control, reduction in appetite, and subsequent weight loss following bypass surgery may be due to
changes in circulating gut hormones.10,12–14
A number of peptides released from the gastrointestinal
tract have recently been shown to regulate appetite and food
intake, effecting both orexigenic and anorexic outcomes
through actions on the hypothalamic arcuate nucleus.15,16
Ghrelin, a hormone produced from the stomach in the preprandial state, increases expression of the orexigenic hypothalamic neuropeptide Y (NPY) and stimulates food intake in
rodents and humans.17,18 In contrast, peptide YY (PYY),
released postprandially from the distal gastrointestinal tract,
acts within the arcuate nucleus to inhibit the release of
NPY19. Intravenous PYY3–36 infusions into humans and intraperitoneal injections into rodents induce satiety and reduce
food intake.19,20 Glucagon-like peptide 1 (GLP-1) acts
mainly as an incretin, promoting postprandial insulin release21 and improving pancreatic -cell function,22 and has
also been reported to inhibit food intake in humans.23 Pancreatic polypeptide (PP) has recently been shown to inhibit
appetite and food intake and promotes energy expenditure.24,25
Annals of Surgery • Volume 243, Number 1, January 2006
Annals of Surgery • Volume 243, Number 1, January 2006
We sought to determine the changes in the enterohypothalamic endocrine axis in human subjects following
bariatric surgery, examining the meal-stimulated release of
PYY, GLP-1, and PP. We used a rodent model of jejunointestinal bypass (JIB) surgery to further examine gut hormone changes and to investigate the potential role of PYY in
mediating the food intake and weight reducing effects of
surgery.
MATERIALS AND METHODS
Human Studies
All human studies were performed according to the
principles of the Declaration of Helsinki. The Local Research
and Ethics committee at King’s College London approved the
bariatric surgery study (02/174). Written informed consent
was obtained from all subjects. Subjects had undergone either
RYGB or an adjustable gastric banding (GB) 6 to 36 months
prior to the study. In this cross-sectional study, patients were
routinely offered a choice of surgical procedures. There was
a small, nonsignificant difference in the preoperative weight
of the RYGB and GB groups (Table 1). The subjects included
in the study had very similar outcomes in terms of weight loss
compared with other patients who had the same obesity
surgery in our clinic but who were not recruited (data not
shown). The RYGB procedures were performed laparoscopically using an omega loop technique as described by Olbers
et al.26 The Roux limb was 112 cm with a 30-mL stomach
pouch and a cut omega loop. GB was performed laparoscopically using the Lap-Band system (BioEnterics). Bands were
positioned in the perigastric area to create a proximal gastric
pouch of approximately 30 mL. Obese control subjects were
recruited following attendance at a surgical obesity clinic.
These obese control subjects had been accepted for surgery
and were on the waiting list for admission; however, they
Gut Hormone Profiles
were not engaged in any active weight loss program. Lean
controls were recruited through local advertising. All control
subjects were at a stable body mass for 3 months prior to this
study. The obese control group was matched for body mass
index (BMI) to the preoperative BMI of surgical patients.
Exclusion criteria included chronic medical or psychiatric
illness, pregnancy, substance abuse, more than 2 alcoholic
drinks per day, and aerobic exercise for more than 30 minutes
3 times per week.
For the meal response studies, subjects were admitted
to the research center after a 12-hour fast, and venous blood
was collected before the meal, 15 minutes after, and at 30
minute intervals up to 3 hours following a mixed 420-kcal
meal. Plasma levels of the gut hormones PYY, GLP-1, PP,
and ghrelin were compared at each time point.
Animal Studies
Animal work was performed under a license issued by the
Home Office UK (PL 70-5569). Male Wistar rats of 387 ⫾
11.7 g were randomized to an established protocol for JIB and
sham bypass (sham) surgery.13 In the JIB group, the jejunum
was divided and anastomosed to the terminal ileum end-toside creating a blind limb. Sham animals underwent division
of the jejunum but with immediate reanastomosis maintaining
normal anatomic continuity. The duration of both procedures
was similar, and each operation lasted between 25 and 30
minutes. Postoperatively, gentamicin 8 mg/kg and carprofen
0.01 mL were administered intraperitoneally (ip) as prophylaxis for postoperative infection.
Animals had ad libitum access to normal rat chow
(RM1 diet, Special Diet Services Ltd, UK) and water unless
otherwise indicated. In each experiment, on the day of termination, animals were fasted for 12 hours from the beginning of the light cycle and were killed at the end of the light
cycle. Blood was obtained, immediately centrifuged at 3000
TABLE 1. Characteristics and PYY, Insulin, GLP-1, Leptin, Ghrelin, and Pancreatic Polypeptide During
the Single 420-kcal Meal Study in Lean, Obese, Bypass, and Banding Subjects
Control Subjects
Single Meal Study
N (females)
Age (yr) 关mean (SD)兴
Baseline BMI (kg/m2) 关mean (SD)兴
Months postoperation 关mean (SD)兴
Postoperation BMI (kg/m2) 关mean (SD)兴
Fasting PYY (pmol/L) 关mean (SD)兴
90 min PYY (pmol/L) 关mean (SD)兴
PYY AUC (pmol/L per min) 关mean (SD)兴
HOMA (IR)
15 min insulin (mUl/L) 关mean (SD)兴
⌬ insulin 15 min (mU/L) 关mean (SD)兴
30 min GLP-1 (pmol/L) 关mean (SD)兴
Fasting leptin (ng/mL) 关mean (SD)兴
Fasting ghrelin (pmol/L) 关mean (SD)兴
30 min PP 关mean (SD)兴
Surgical Patients
Lean
Obese
Bypass
Banding
P
15 (13)
34.8 (8.90)
23.8 (3.03)
12 (9)
37.9 (5.54)
47.1 (5.76)
15.4 (8.3)
23.7 (9.5)
1308 (552)
1.36 (1.12)
9.15 (7.06)
3.3 (6.9)
20.2 (9.0)
6.3 (3.3)
700.6 (60.7)
44.5 (24.2)
13.8 (7.1)
16.0 (8.1)
633 (267)
4.22 (1.65)
18.4 (9.64)
2.6 (9.8)
13.5 (6.9)
16.5 (4.3)
446.1 (117.6)
59.1 (52.1)
6 (6)
39.3 (3.6)
49.8 (10.8)
11.2 (6.5)
36.8 (7.56)
18.5 (5.2)
40.4 (7.8)
3082 (670)
1.94 (1.16)
30.3 (15.2)
22.3 (15.9)
47.4 (11.3)
10.2 (2.2)
430.4 (53.2)
43.2 (44.4)
6 (6)
40.3 (10.7)
46.1 (4.59)
19.2 (3.3)
36.3 (4.15)
12.9 (6.1)
18.0 (8.9)
913 (393)
1.46 (1.05)
11.6 (11.9)
3.8 (7.3)
14.0 (6.2)
11.1 (2.7)
491.3 (120.8)
63.0 (44.1)
NS
P ⬍ 0.05
P ⬍ 0.05
NS
NS
⬍0.001
⬍0.0001
⬍0.0001
⬍0.01
⬍0.01
⬍0.01
⬍0.05
⬍0.05
NS
NS indicates not significant.
© 2005 Lippincott Williams & Wilkins
109
Annals of Surgery • Volume 243, Number 1, January 2006
le Roux et al
rpm for 10 minutes at 4°C, and stored at ⫺20°C until
analysis.
In accordance to previously published protocol,13 rectal
temperature was measured preoperatively, 10 and 26 days
after the operation in conscious restrained rats. Measurements
of C-reactive protein and white blood cell counts were made
to assess inflammation. To evaluate malabsorption, fecal
material was collected on day 20 and 26 from the JIB, sham
bypass and pair fed groups. The feces were dried in an oven
and weighed; calorie content was measured using a ballistic
bomb calorimeter.27
Ten days after the operation, 6 JIB rats received ip
injections 1 hour before the dark phase of purified PYY rabbit
antibody (0.2 mL). In these experiments, control sham rats
received 0.2 mL of purified nonimmune rabbit serum. Food
intake was measured at 1, 2, 4, 8, 12, and 24 hours following
injection.
Where indicated, rodent PYY3–36 (5 g/100 g; Bachem
UK) was administered ip as a 0.2 mL solution with 0.9%
saline, 1 hour before the beginning of the dark phase. JIB
animals received 0.2 mL of 0.9% saline ip. In the chronic
exposure experiment, 5 g/100 g PYY3–36 was given ip as a
0.2-mL solution with 0.9% saline to the sham rats 1 hour
before the beginning of the dark phase for 10 days and then
twice daily for a further 8 days, 1 hour before the onset of the
dark or light phase. The JIB rats received 0.2 mL of 0.9%
saline ip. Food intake was measured daily for 28 days.
Hormone Assays
All samples were assayed in duplicate. PYY-like immunoreactivity was measured with a specific and sensitive
radioimmunoassay, which measures, both the full length
(PYY1–36) and the fragment (PYY3–36).20,28 GLP-1 and PP
were measured in duplicate by established in-house radioimmunoassays.21,29 Plasma immunoreactive ghrelin was measured in duplicate with the commercially available Phoenix
Pharmaceutical assay kit and plasma leptin with a Linco
Research assay kit. Insulin (Abbott, UK) and glucose (Olympus, UK) were measured using commercial immunoassays.
Statistical Analysis
Hormone levels are expressed as means ⫾ SD. Values
for the area under the curve were calculated with the use of
the trapezoidal rule. End points were compared with the use
of 2-tailed, paired Student t tests or ANOVA, and exact
binomial methods were used where indicated (Graphpad
Prism, USA).
RESULTS
Human Studies
The characteristics of the lean (n ⫽ 15), obese (n ⫽ 12),
RYGB (n ⫽ 6), or GB (n ⫽ 6) patients are shown in Table 1.
Control obese subjects were matched to the preoperative BMI
of patients in the surgical groups. Patients with either operation had an equivalent postoperative BMI, although the
duration following the procedure was greater for the GB
patients. Fasting leptin levels were equivalent in the RYGB
and GB subjects (P ⫽ 0.68), and although lower than obese
110
control subjects, leptin levels were significantly higher than
lean subjects (P ⬍ 0.05) (Table 1).
Two patients in the RYGB and 2 in the GB group had
diabetes before the surgery, but no patient satisfied the WHO
criteria for diabetes at the time of the study. Obese subjects
demonstrated elevated fasting insulin and basal insulin resistance (assessed by HOMA),30 whereas postsurgical subjects
were found to be as insulin sensitive as lean subjects, despite
a significantly higher BMI postoperatively. Subjects did not
experience hypoglycemia or symptoms of the dumping syndrome following a test meal, and all postprandial glucose
values were above 4.4 mmol/L. Significant differences were
observed between groups in the dynamic insulin response to
a mixed meal. In the RYGB group, an early rise in insulin
secretion was observed (Fig. 1A) with a significantly higher
increase in plasma insulin at 15 minutes compared with the
GB, lean and obese subjects (P ⬍ 0.001; Table 1; Fig. 1B).
The pronounced early insulin peak in RYGB patients
prompted further investigation of the release of the incretin, GLP-1. In response to a 420-kcal meal, lean control
subjects achieved a 30-minute GLP-1 level of 20.2 ⫾ 9.0
pmol/L (66% above baseline, P ⫽ 0.02) (Table 1; Fig. 1C).
However, RYGB patients had an exaggerated GLP-1 response of 47.4 ⫾ 11.3 pmol/L (230% above baseline, P ⬍
0.001), significantly higher than other groups (P ⬍ 0.001,
Fig. 1C). In contrast, obese control subjects exhibited an
attenuated response (13.5 ⫾ 6.9 pmol/L, 22% above baseline,
P ⫽ 0.1). GB subjects achieved GLP-1 levels of 14.0 ⫾ 6.2
pmol/L (50% above baseline) equivalent to obese controls.
Similar to GLP-1, following the test meal, plasma PYY
concentrations were exaggerated in the RYGB patients. Lean
control subjects achieved a 90-minute PYY level of 23.7 ⫾
9.5 pmol/L (49% above baseline, P ⬍ 0.01; Table 1; Fig.
1D). RYGB patients had an exaggerated PYY response of
40.4 ⫾ 7.8 pmol/L (162% above baseline, P ⬍ 0.001) and
significantly higher than lean subjects, (P ⫽ 0.002; Fig. 1D).
In contrast, PYY did not rise postprandially in obese control
subjects (16.0 ⫾ 8.1 pmol/L, 14% above baseline, P ⫽ 0.19),
while GB subjects achieved PYY levels of 18.0 ⫾ 8.9 pmol/L
(22% above baseline, P ⫽ 0.001, no different from lean
subjects, P ⫽ 0.37). PP response was similar in all 4 groups
(Table 1).
Fasting ghrelin levels in the lean group were 700.6 ⫾
15.5 pmol/L (Table 1), whereas obese control subjects had a
lower fasting ghrelin of 446.1 ⫾ 41.9 pmol/L (P ⫽ 0.002).
We found no differences in the fasting ghrelin levels among
the obese and surgical treated groups (Table 1).
Animal Studies
To further evaluate the potential importance of the
observed hormonal responses in human subjects, an established rat model of bariatric surgery was used in which rats
either received a JIB or a sham bypass.13 Although anatomically distinct, like the RYGB, the JIB procedure bypasses a
significant segment of small bowel. The JIB differs from the
RYGB in that there is no reduction in stomach size, which
gives a restrictive component to the RYGB. In the immediate
4 days postoperatively, both JIB and sham rats had comparable weight loss. At day 8, however, the sham animals
© 2005 Lippincott Williams & Wilkins
Annals of Surgery • Volume 243, Number 1, January 2006
Gut Hormone Profiles
FIGURE 1. A, The insulin response,
C, GLP-1 responses and D, PYY response to test a meal in RYGB (Œ),
GB (■), lean (〫), and obese (O)
subjects. B, The insulin increment
between baseline and 15 minutes
in the 4 groups.
returned to baseline weight, which continued to increase on
ad libitum feeding (Fig. 2A). In contrast, JIB animals lost
20% of their preoperative weight at day 8 and then achieved
a plateau around 314 ⫾ 11 g. This was significantly lower
than the final weight of 464 ⫾ 9 g in the sham rats (P ⬍
0.001). Interestingly, the food consumption followed similar
patterns but was consistently lower in the JIB group (Fig.
2B). Another group of sham animals (n ⫽ 6) were pair-fed to
the JIB group for 28 days (Fig. 2A). The pair-fed sham rats
weighed significantly more than the JIB animals; therefore,
infection or malabsorption was evaluated among the bypass
animals.
Malabsorption was investigated by fecal weight and
fecal calorie content using bomb calorimetry. There was no
evidence for an increase in either fecal mass or fecal calorie
content in the JIB animals, thus excluding malabsorption as a
major cause for the weight loss (Table 2). Survival after
surgery was similar in both groups, and there was no evidence of an inflammatory response reflecting anastomotic
leakage since body temperature, C-reactive protein, and neu-
trophil count were similar in both groups (data not shown).
An inference can be drawn that energy expenditure may be
influenced by surgery, although we were unable to measure
this directly in this study.
The potential role of gut hormones on mediating the
observed weight loss following JIB surgery was determined.
Figure 3 demonstrates that the JIB rats had significantly
higher fasting plasma levels of both PYY and GLP-1. To
further evaluate the potential causative effect of the increase
in PYY following JIB surgery, two experimental paradigms
were used. First, a PYY neutralizing antibody was injected
into JIB animals in an attempt to abrogate the effect of
surgery. Second, PYY levels were raised through exogenous
PYY administered in the sham animals. In a preliminary
study, following injection of neutralizing antibody, JIB rats
ate significantly more than the previous day (30.0 ⫾ 1.0 g
versus 25.0 ⫾ 1.9 g, P ⫽ 0.04), whereas there was no
difference in food consumed for 24 hour in sham rats after
injection of control serum (30.3 ⫾ 0.8 g versus 29.4 ⫾ 1.6 g,
P ⫽ 0.54). Elevating circulating PYY in another group of
FIGURE 2. A, The weight changes
for the JIB (--■--) (n ⫽ 12), sham
bypass (B) (n ⫽ 12), and sham
bypass pair fed (…Œ…) (n ⫽ 10)
rats over 28 days. B, The average
daily food intake of the JIB (--■--)
and sham bypass (B) rats over 28
days. *P ⬍ 0.05.
© 2005 Lippincott Williams & Wilkins
111
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le Roux et al
TABLE 2. Dry and Wet Weight of Fecal Material Collected on Day 20 and 26 From the
BP (n ⫽ 6), Sham Bypass (n ⫽ 6), and Pair-Fed (n ⫽ 6) Rats, as Well as the Energy
Content (calories) of the Fecal Material
Feces
Wet weight day 20 (g)
Wet weight day 26 (g)
Dry weight day 20 (g)
Dry weight day 26 (g)
Fecal calorie content day 20 (kcal)
Fecal calorie content day 26 (kcal)
Sham Bypass
(mean ⴞ SD)
Sham Bypass
Pair Fed
(mean ⴞ SD)
JIB (mean ⴞ SD)
P
7.7 ⫾ 0.5
6.7 ⫾ 0.3
6.7 ⫾ 0.4
5.9 ⫾ 0.3
22.0 ⫾ 1.9
20.2 ⫾ 1.5
8.8 ⫾ 0.7
4.8 ⫾ 0.4
7.1 ⫾ 0.3
4.4 ⫾ 0.3
21.8 ⫾ 1.5
14.6 ⫾ 0.8
7.7 ⫾ 0.5
5.7 ⫾ 0.8
6.4 ⫾ 0.3
4.8 ⫾ 0.5
23.3 ⫾ 1.2
18.2 ⫾ 1.9
NS
NS
NS
NS
NS
NS
NS indicates not significant.
sham rats was achieved by daily administration of PYY from
day 10 to 20 and then twice daily for days 21 to 28. Mean
food intake after the 10th day postoperatively among saline
treated JIB rats were 32.2 ⫾ 1.0 g/d, which was similar to the
PYY treated sham rats that ate 31.8 ⫾ 1.3 g/day (P ⫽ 0.76).
DISCUSSION
The RYGB leads to a reduced obese state with the
anticipated changes in fuel homeostasis, but without the
compensatory increased appetite that usually leads to weight
regain following most forms of intentional weight loss. We
have demonstrated a pleiotropic endocrine response to bariatric surgery, which might account for the appetite reduction
that leads to long-term changes in body weight. We have
shown that following RYGB, patients have increased postprandial PYY and GLP-1 favoring enhanced satiety to a
meal. Furthermore, RYGB patients had early and exaggerated
insulin responses, potentially mediating the improved glycemic control in patients with T2DM. None of these effects
were observed in patients losing similar weight through GB,
suggesting that the hormonal changes are not secondary to
weight loss alone. We further demonstrated in a rodent model
of intestinal bypass that elevated PYY may have a causative
role in mediating reduced food intake.
Weight loss following JIB surgery is due to decreased
appetite and calorie intake,31 and clinical malabsorption is not
usually a feature of RYGB.32 PYY, a gut hormone with
highest tissue concentrations in distal segments of the gastrointestinal tract, is released into the circulation proportional
to food intake.33 Chronically elevated fasting levels of PYY
have been described in several gastrointestinal diseases asso-
ciated with loss of appetite.34,35 Established actions of PYY
include reduced gastric emptying, delayed gastrointestinal
transit,36 reduced food intake,19,20 and may be a major factor
influencing postprandial satiety.15,37 All of these actions
could be considered an appropriate response to acute small
intestinal disease or shortened small bowel as they would
decrease the nutrient load and increase absorption time.
Following RYGB, postprandial PYY concentrations were
elevated to levels previously shown to have appetite-reducing
effects.19,20 We propose that the higher postprandial PYY
response after gastric bypass surgery due to the altered
intestinal anatomy may contribute to the patients’ increased
satiety and weight loss. RYGB is thought to be significantly
more effective than restrictive procedures such as vertical
banded gastroplasty for weight loss in morbid obesity, especially for patients addicted to sweets.38 The banding patients
did not have an exaggerated PYY response. There are no
direct comparisons of satiety between RYGB and GB, although reports indicate that patients do experience sensations
reported as enhanced satiety after GB39,40 and RYGB.41,42
Our studies in humans fall short of establishing changes
in PYY as having a mechanistic role in the appetite changes
and weight loss after RYGB. To investigate a potential
causative role for PYY, we used an established rodent model
of JIB.13 At the time of the experiments, JIB was the only
established model of bariatric surgery in rodents. Both JIB
and RYGB lead to weight loss and reduced food intake,32,41,42 which were previously suggested to be due to a
hormonally mediated mechanism.13 Thus, despite the species
and surgical procedure being different, the rodent model of
intestinal bypass was used to examine the mechanisms for
FIGURE 3. Fasting plasma PYY and GLP-1 levels in
the sham bypass (y) (n ⫽ 6) and JIB (x) rats (n ⫽ 6).
*P ⬍ 0.05.
112
© 2005 Lippincott Williams & Wilkins
Annals of Surgery • Volume 243, Number 1, January 2006
weight loss in RYGB patients. Both the humans and the
rodents show reduced food intake and weight loss, while
plasma PYY and GLP-1 were elevated. In a preliminary
rodent study, a specific neutralizing PYY antibody resulted in
an increased food intake in the bypass rats, while the nonimmune serum in the sham bypass rats caused a nonsignificant
reduction. Exogenous administration of PYY to the sham
bypass rats led to a reduction in food intake to a similar level
seen in the bypass group. These results are consistent with
PYY having a role in enhancing satiety following intestinal
bypass surgery. Note, however, that findings in the JIB rodent
model cannot be directly extrapolated to the human RYGB,
which has an additional restrictive component over and above
the potential effect of an exaggerated PYY response. The
previous data reported in humans after JIB showing elevated
fasting and postprandial PYY concentrations43 are, however,
consistent with the findings in both our rodent model of JIB
and human model of RYGB. The lower body weight in the
bypass group was not due to decreased food intake alone, as
the sham bypass pair fed group weighed more than the bypass
group. The difference in weight despite the same food intake
raises the possibility of enhanced energy expenditure following intestinal bypass surgery. These observations will require
further investigation.
In both rodent and human studies, high GLP-1 was
observed in parallel with PYY. GLP-1 is produced from the
same entero-endocrine cells (L cells) as PYY and acts as an
incretin, releasing insulin21 and improving pancreatic -cell
function in rodents.22 Reduction in food intake has also been
reported.44 Previously, increased GLP-1 concentrations have
been shown following intestinal bypass.9,43 Consistent with
previous RYGB studies, our study found no difference in
fasting GLP-1 levels11 but demonstrates an exaggerated
GLP-1 response following a 420-kcal meal in gastric bypass
subjects. The increased GLP-1 response may contribute as a
satiety signal and incretin. Glycemic control in T2DM patients improves following RYGB surgery7,10,11 and often
before significant weight loss occurs.10 A recent study in a
nonobese diabetic rodent model following duodenal-jejunal
exclusion demonstrated improvement in glycemic control
that appeared independent of weight loss.14 Following weight
loss, lower body weight per se most likely also contributes to
improved insulin sensitivity.12
The normal postprandial glucose concentrations in all
the individuals studied here are consistent with the absence of
symptoms of the dumping syndrome. Although the BMI of
both the bypass and banding patients was in the obese range,
the fasting glucose homeostasis (HOMA) was similar to that
observed in the lean control subjects. However, the RYGB
group had significantly higher insulin levels 15 minutes after
the meal, which might partly explain the improvement in
glycemic control observed in other studies.7,10,11 The early
and increased release of insulin in the bypass patients may be
mediated by direct action of nutrients in the jejunum and/or a
hormonal signal such as GLP-1.
Ghrelin, produced in the stomach, was initially associated with appetite reduction following gastric bypass.12 The
reduced appetite following gastric bypass was explained by
© 2005 Lippincott Williams & Wilkins
Gut Hormone Profiles
the failure of ghrelin to show the expected rise observed in
diet-induced weight loss.12,45 However, a series of publications have since shown inconsistent ghrelin changes after
RYGB and GB. These studies have recently been reviewed,
and the heterogeneity of the findings makes it unlikely that
ghrelin has a major role in the weight loss after RYGB.46 In
our study, compared with lean control subjects, both bypass
and banding patients had lower fasting ghrelin levels, although these were similar to those of the obese control
subjects. In agreement with the majority of studies, we did
not find an anticipated compensatory rise in ghrelin among
surgical subjects.
Our data show that patients treated for obesity with
gastric bypass therefore have alterations of several peripheral
signals that potentially contribute to their reduced appetite
and enhanced glucose homeostasis. An exaggerated postprandial PYY and GLP-1 might combine to enhance satiety,
leading to a long-term reduction in calorie intake, while
increased GLP-1 and insulin might contribute to immediate
improvements in glycemic control.
Our studies demonstrate that obese subjects treated with
GB had equivalent weight loss and improvements in insulin
resistance as measured by HOMA to bypass patients, but did not
have the postprandial insulin or gut hormone responses indicating that the endocrine changes are a consequence of the particular type of surgery rather than weight loss. Although it has
been suggested that bypass operations are more effective,47
restrictive procedures undoubtedly cause significant weight
loss39 and affect appetite. It remains to be established whether
neural mechanisms possibly through vagal afferents are involved in mediating increased satiety following GB.
The obese subjects in our study had a blunted postprandial PYY and GLP-1 response, which may reflect a functional
deficiency state. Following bypass surgery, it is likely that
multiple mechanisms act in concert to achieve sustainable
weight loss. Our rodent model indicates that, although PYY
may contribute, other additional hormonal and/or neural factors may be involved. Replicating the endocrine milieu that
arises as a consequence of gastric bypass surgery through
pharmacologic means holds promise for future medical intervention in morbid obesity.
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