The neurohormonal regulation of energy intake in relation to bariatric surgery
Christopher N. Ochnera,b,⁎, Charlisa Gibsona, Susan Carnella, Carl Dambkowskia, Allan Geliebtera,b
aNew York Obesity Research Center, St. Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY 10025, USA
bDepartment of Psychiatry, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA
a b s t r a c ta r t i c l ei n f o
Received 19 January 2010
Received in revised form 25 March 2010
Accepted 28 April 2010
Obesity has reached pandemic proportions, with bariatric surgery representing the only currently available
treatment demonstrating long-term effectiveness. Over 200,000 bariatric procedures are performed each
year in the US alone. Given the reliable and singular success of bariatric procedures, increased attention is
being paid to identifying the accompanying neurohormonal changes that may contribute to the resulting
decrease in energy intake. Numerous investigations of postsurgical changes in gut peptides have been
conducted, suggesting greater alterations in endocrine function in combination restrictive and malabsorptive
procedures (e.g., Roux-en-Y gastric bypass) as compared to purely restrictive procedures (e.g., gastric
banding), which may contribute to the increased effectiveness of combination procedures. However, very
few studies have been performed and relatively little is known about changes in neural activation that may
result from bariatric procedures, which likely interact with changes in gut peptides to influence postsurgical
caloric intake. This review provides a background in the neurohormonal regulation of energy intake and
discusses how differing forms of bariatric surgery may affect the neurohormonal network, with emphasis on
Roux-en-Y gastric bypass, the most commonly performed procedure worldwide.
The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for
the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.
© 2010 Elsevier Inc. All rights reserved.
Currently, bariatric surgery represents the only form of treatment
for obesity that demonstrates long-term effectiveness [1–3]. From
1992 to 2006, a ten-fold increase in obesity surgeries was observed
. The most common forms of bariatric surgery are Roux-en-Y
gastric bypass (RYGB) and adjustable gastric banding (AGB), which
together account for approximately 90% of the procedures performed
today . Postsurgical reductions in body weight result largely from
the restrictive and/or malabsorptive effects of the bariatric proce-
dures. However, these mechanisms alone appear to be insufficient to
account for the reductions in caloric intake and body weight seen
postsurgically [6–8], evenin purelyrestrictiveprocedures suchas AGB
[7,9]. Alterations in the neurohormonal regulation of energy intake
have been proposed to contribute to postsurgical reductions in caloric
intake, particularly in RYGB [8,10–12].
1. Hormonal influences on energy intake regulation relevant to
Numerous hormones are involved in controlling appetite and
food intake via the activation of brain areas, primarily within the
limbic and mesolimbic systems . Hunger and satiety signals from
adipose tissue (leptin), the pancreas (insulin) and the gastrointestinal
tract (cholecystokinin [CCK], glucagon-like peptide-l [GLP-1], peptide
YY3–36[PYY3–36]) are involved in relaying information about energy
status through the neurohormonal gut–brain axis primarily targeting
the hypothalamus and brainstem . The major appetite-related
peptides, which act through the central nervous system (CNS) to help
regulate energy balance and may be affected by bariatric surgery, are
Secreted mainly by the stomach, ghrelin is an orexigenic peptide
that acts on hypothalamic neurons through the bloodstream via vagal
afferents containing ghrelin receptors, as well as through direct
release within the hypothalamus . In animals, central ghrelin
Physiology & Behavior 100 (2010) 549–559
⁎ Corresponding author. NY Obesity Research Center, St. Luke's-Roosevelt Hospital
Center, 1111 Amsterdam Avenue, Babcock 1020, New York, NY 10025, USA. Tel.: +1
212 523 2350; fax: +1 212 523 4830.
E-mail address: email@example.com (C.N. Ochner).
0031-9384/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
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administration also enhances the secretion of the orexigenic neuro-
peptides neuropeptide-Y (NPY) and agouti-related peptide (AgRP) in
the arcuate nucleus (AN) of the hypothalamus . Ghrelin has also
been shown to activate dopamine neurons in the ventral tegmental
area (VTA) and promote dopamine turnover in the nucleus accum-
bens (NA) of the ventral striatum . This effect on reward
processing in the mesolimbic dopaminergic pathway may be an
integral part of ghrelin's orexigenic action [17,18], supported by
evidence that blocking ghrelin receptors in the VTA decreases food
1.2. Peptide YY (PYY)
L entero-endocrine cells . PYY mediates its actions via Y1–Y5
receptors on vagalafferents leads to activation of thearcuate nucleus to
suppress NPY activation . Delayed gastric emptying (via the ileal
appetite and food intake .
1.3. Glucagon-like peptide 1(GLP-1)
Co-released with PYY, GLP-1 is an anorexigenic peptide that is
secreted postprandially from the distal gastrointestinal tract. GLP-1
acts as an ileal brake for the upper GI tract and decreases food intake
in part by inhibiting gastric emptying, resulting in greater gastric
distension . Endogenous GLP-1 affects hypothalamic signaling
through vagal afferent neurotransmission [23,24] and by entering the
peripheral circulation. Circulating levels of GLP-1 are higher prior to
and following food consumption in lean as compared to obese
An endogenous hormone present in the GI tract and the brain,
cholecystokinin (CCK) helps control meal size and duration via a
feedback signaling network involving the periphery and the CNS
. CCK reaches peak levels within 15–30 min [27,28]. CCK
activates receptors on the vagus nerve, which transmit satiety
signals to the dorsomedial hypothalamus and minimizes NPY action
An anorexigenic hormone synthesized from adipose tissue, leptin
helps control adipose metabolism by stimulation of lipolysis and
suppression of lipogenesis . It crosses the blood brain barrier and
transmits signals about metabolic status from the periphery to
hypothalamic regulatory centers . Once bound to its central
receptor, leptin down-regulates appetite stimulating neuropeptides
(e.g., NPY, AgRP) while up-regulating anorexigenic alpha-Melano-
cyte-stimulating hormone, cocaine-and amphetamine-regulated
transcript and corticotropin-releasing hormone . Leptin injections
in obese humans have not been efficacious in reducing food intake
and weight gain, potentially due to the development of leptin
resistance . Studies also suggest that leptin can influence the
reward value of food [32,33] and leptin administration can help
maintain lost weight .
Secreted from the pancreas, insulin varies directly with adiposity,
and visceral fat is negatively correlated with insulin sensitivity
. Basal and postprandial insulin are greater in obese than in
lean individuals . Insulin can penetrate the blood brain barrier
and binds to receptors in the AN to decrease food intake . See
Table 1 for a brief summary of the major appetite-related peptides
relevant to bariatric surgery and their proposed effects on hunger or
2. Neuroimaging and energy intake regulation in relation to
Neuroimaging is increasingly becoming more common in obesity
research as investigators attempt to understand the biological basis of
eating behavior. Positron emission tomography (PET), single photon
emission computed tomography (SPECT), and functional magnetic
resonance imaging (fMRI) are common neuroimaging techniques
used to assess brain activity and provide insight into brain systems
linked to feeding behavior (See  and  for reviews).
but can be roughly divided into two related systems, the homeostatic
and hedonic networks [12,17]. The homeostatic system is comprised of
the hypothalamus and brainstem, driven mainly by hypothalamic
activity [12,17]. The hypothalamus, especially the arcuate nucleus,
integrates peripheral hormonal signals and receives inputs from the
brainstem, which detects vagal signals related to ingestion . It is
responsible for the assimilation of input about internal hunger and
relevant brain areas (e.g., upward moderation of mesolimbic reward
areas to increase the reward salience of food during caloric deprivation)
need in order to maintain energy balance and body weight [17,42],
which may be determined by a biological settling point .
In contrast, the hedonic system drives food intake based on the
perceived reward value of food [17,44], operating largely through
dopaminergic signaling in the mesolimbic pathway . The
mesolimbic pathway initiates behavioral responses based on the
predicted reward, or hedonic, value of stimuli encountered in the
environment [12,44]. Major components of this complex neural
system include the amygdala, hippocampus, VTA, and striatum
(caudate, NA, and lentiform nucleus), and these areas have strong
functional connections to areas within the prefrontal cortex (PFC; e.g.,
dorsolateral PFC, orbitofrontal cortex [OFC]) . The PFC is
responsible for integrating internal and external sensory information,
reward-related information from other cortico-limbic areas and
signals from the hypothalamus, which can modulate reward salience
[13,17]. The PFC is also connected to other cortical areas involved in
motor planning and execution .
The relatively limited number of studies that have examined brain
activation in relation to food intake or body weight are mainly cross-
sectional and focus on the differences in reaction to food stimuli
between types of stimuli (e.g., high vs. low-palatability) or body mass
index (BMI; e.g., lean vs. obese)[47,48]. The majority of studies in this
area coalesce in reporting greater activation in hedonic system activa-
Major appetite-related peptides relevant to bariatric surgery.
Gut peptidesCentral effects on appetite Alterations due to RYGBa
↑ = increase. ↓ = decrease. → = no significant change.
↔ = modifies effect depending on energy balance.
aAccording to the majority of study findings to date.
C.N. Ochner et al. / Physiology & Behavior 100 (2010) 549–559
individuals [49,50]. Such findings potentially reflect greater perceived
hedonic reward of high (vs. low) palatability food cues and heightened
sensitivity to reward in obese (vs. lean) individuals [51,52].
As noted, reward value is largely processed in the PFC, which
receives visual, auditory, and orosensory inputs from the thalamus, as
well as information from the hypothalamus . There is evidence to
suggest that the hypothalamus may modulate reward salience [53–55],
which may explain why individuals in a state of caloric need (fasted)
[56,57], as well as greater activation of hedonic network brain areas in
response to appetitive stimuli [54,58,59]. Conversely, in a fed state (in
the presence of postprandial satiety signals), individuals show de-
creased hedonic network activation in response to appetitive stimuli
[54,59]. However, the hedonic system can override attempts by the
homeostatic system to maintain energy balance, and drive food intake
even in the presence of postprandial satiety signaling [60,61]. Variation
in the ease with which satiety signals are overridden by the perceived
reward value of food may reflect individual differences in appetitive
responsivity, or the desire to eat following exposure to food cues .
3. Interactions between gut peptides and brain systems relevant
to bariatric surgery
Neurological and hormonal systems are often studied indepen-
dently, but hunger and satiety signals are mediated by a complex
interplay of both systems, the neurohormonal pathway . Ghrelin,
PYY, GLP-1, CCK, insulin and leptin are primarily released in the
periphery in response to the presence or absence of nutrients in the
digestive tract [63,64] but act indirectly on the vagus nerve and/or
directly on target areas of the hypothalamus , propagating potent
hunger and satiety signals to the brain. In addition, gut peptide
signaling may have more complex neurobehavioral actions in
triggering hypothalamic modulation of the perceived reward value
of food via the mesolimbic pathway . See Fig. 1.
3.1. Neuroimaging and appetite-related hormones
A novel technique for examining in vivo gut–brain interactions in
humans is to combine neuroimaging with gut hormone measures or
manipulations. Farooqi et al.  used fMRI to show that heightened
activation in the ventral striatum in response to food cues in two
leptin-deficient adolescents was significantly reduced following one
week of leptin administration. In other fMRI studies, Rosenbaum et al.
 showed that a number of changes in brain activation typically
associated with increased hunger, which resulted from non-surgical
weight loss, were leptin-reversible. Similarly, Baicy et al.  reported
reduced brain activity in regions linked to hunger (insula, parietal and
temporalcortex)in geneticallyleptin-deficient adultsfollowingleptin
replacement. These studies are consistent with evidence suggesting
that leptin may suppress appetite by down-regulating brain areas
associated with drive to eat while up-regulating areas associated with
homeostatic control and satiety [33,67].
In an fMRI study of ghrelin infusion, Malik et al.  found post-
infusion increases in activation in the amygdala, OFC, insula and
striatum in response to pictures of highly palatable food in lean males
given a 20 min ghrelin infusion, suggesting that some portion of
ghrelin's orexigenic effects may come through the enhancement of
the perceived reward value of food. Animal studies [18,70] further
implicate an interaction between ghrelin and mesolimbic pathway
activation in showing that ghrelin can activate dopamine neurons in
the VTA and increase dopamine in the nucleus accumbens, which may
stimulate food intake [15,16].
Ina studyof food-induced hormonalchanges,Pannacciulli et al. 
a satiating amount of a liquid formula meal to lean adult subjects.
Postprandial increases in GLP-1 were found to correlate positively with
increases in activity in the dlPFC and hypothalamus, suggesting that
GLP-1 may mediate the purported role of the dlPFC in the cessation of
eating (satiety signaling) [71,72]. Finally, in an innovative study of real-
time interactions between changes in gut hormone levels and brain
activation, Batterham et al.  infused PYY3–36at a rate designed to
brain activation concurrently, using fMRI. These authors showed that
increases in PYY3–36were associated with increased activity in the OFC,
parabrachial nucleus, midbrain VTA, insula, anterior cingulate, ventral
striatum and posterior hypothalamus. They also reported a PYY3–36-
induced shift from homeostatic (hypothalamic) to hedonic (OFC) brain
areas in predicting subsequent food intake, which may reflect a switch
a postprandial satiety signal.
Fig. 1. Cartoon representation of the relevant influences on energy intake. The strength of evidence in support of each association is represented by the thickness of the connecting
arrows with bolded lines representing strong empirical support and the dotted lines representing more theoretical evidence.
C.N. Ochner et al. / Physiology & Behavior 100 (2010) 549–559
4. Surgical interventions for obesity
Surgical interventions are not only more effective than behavioral
treatments in the short term but are the only form of obesity
intervention with evidence of consistent long-term effectiveness
[1,3]. Current surgical interventions for obesity all contain a restrictive
component, limiting the amount of food that can enter the stomach
pouch as well as the rate at which food can be ingested. Several
procedures, most notably RYGB, also contain a malabsorptive part in
which the bowel length is shortened, decreasing nutrient and calorie
absorption. However, there is controversy regarding the degree and
durability of postsurgical malabsorption associated with these
procedures . The purely restrictive AGB procedure is gaining
popularity, currently representing approximately 25% of procedures
[1,75], second only to RYGB, which accounts for approximately 65% of
procedures worldwide . Gastric bypass results in more weight loss
than gastric banding (GB). The Swedish Obese Subjects  study
showed that the maximal percent of initial weight lost (1–2 yr post-
surgery) was 32%±8 SD in RYBG vs. 20%±10 in GB and this
difference was maintained at 10 yr follow up (25% in RYGB vs. 14% in
GB). Similarly, at 2-yr follow up, Shah et al.  reported reductions of
approximately 31% of initial body weight in RYGB vs. 24% in GB.
Descriptions of these and other procedures are provided below.
Most purely restrictive procedures create a small gastric pouch with
a narrow outlet, limiting the intake of food without disruption of the
absorptive function of the small intestine. With VBG, a longitudinal
staple line with a tight outlet wrapped by a band or mesh partitions the
cardia (proximal part) from the rest of the stomach (Fig. 2A), whereas
AGB involves encircling the upper part of the stomach (distal to the
gastroesophageal junction) with a tight, adjustable, prosthetic band
(Fig. 2B). The amount of restriction in AGB may be altered by the
addition or withdrawal of saline solution from the hollow core of the
band . Sleeve gastrectomy, intragastric balloon, and endoluminal
gastroplasty are other forms of restrictive procedures that are less
commonly used. Conventional malabsorptive bariatric operations
predominantly circumvent a portion of the small intestine in an effort
of a purely malabsorptive technique, which separates the jejunum near
the ligament of Treitz and reconnects it near the ileocecal valve,
bypassing a long small bowel segment (Fig. 3A). However, this
procedure is rarely performed due to significant complications and
relatively greater need for revision surgeries .
Combination bariatric procedures incorporate both restrictive and
malabsorptive components. Biliopancreatic diversion (BPD) consists
of a distal horizontal gastrectomy, where the remnant stomach is
anastomosed to the distal small intestine (alimentary limb). The
excluded small intestine carries the bile and pancreatic secretions,
and is anastomosed to the short bowel channel proximal to the
ileocecal valve, leaving a short common limb portion for the mixing of
nutrients with secretions (Fig. 3B). The BPD is also limited in use due
to adverse health outcomes related to essential nutrient malabsorption
. The biliopancreatic diversion with duodenal switch (BPD-DS)
resected, with duodenal closure a few centimeters distal to an intact
pylorus facilitating a duodeno-ileal anastomosis (Fig. 3C). This proce-
dure is chieflyperformed on super-obese patients (BMIsN50 kg/m2),as
is not commonly performed due to adverse health outcomes similar to
those seen in BPD . Lastly, RYGB surgery represents the most
common bariatric procedure and is considerably more effective than
AGB. With RYGB, a small gastric pouch is created and anastomosed to
the jejunum with a short Roux-en-Y alimentary limb of distal small
a portion of the jejunum (Fig. 2C).
Despite a rapid increase in the number of studies on bariatric
surgery, the precise mechanisms of action are still not well
understood, particularly with RYGB [8,80]. While the restricted (15–
50 mL) postsurgical pouch size limits ingestive capacity  and the
bypassing of the upper portion of the small intestine may prevent a
small percentage of ingested calories from being absorbed into the
body [8,74], these mechanisms account for only a proportion of
postsurgical weight loss [8,10,81]. Evidence for this comes from
research demonstrating corrective adaptation to the malabsorptive
component  and limited small meal adaptation , as well as
subjective reports [83,84] and behavioral data [85,86] suggesting that
presurgical preferences for foods high (vs. low) in fat , calories
, and palatability [83,87] are reduced or eliminated following
RYGB (but not AGB) surgery. Finally, preliminary data from our
laboratory suggest that there may also be a greater reduction in non-
specific (to any particular food) desire to eat in response to high-
calorie, relative to low-calorie food cues following RYGB. The
neurohormonal system has been repeatedly implicated in accounting
for this unexplained reduction in postsurgical caloric intake [8,10–12].
Numerous investigations of appetite-related gut peptides have
resulted and are described below.
5. Alterations in gut peptides involved in energy intake regulation
through bariatric surgery
Ghrelinis produced primarily bythegastric antrumand fundusand,
although the anterior section of the stomach is reduced in purely
ghrelin levels after surgical intervention. In some studies, lower fasting
ghrelin levels were reported after laparoscopic sleeve gastrectomy (SG)
[88,89]; while other findings showed increases in fasting ghrelin
following LAGB [90–92]. A rise in ghrelin concentrations following
Fig. 2. Illustrations of restrictive procedures and Roux-en-Y gastric bypass. Reproduced with permission from Dr. Edward C Mun  A. Vertical banded gastroplasty; B. Adjustable
gastric banding; C. Roux-en-Y gastric bypass.
C.N. Ochner et al. / Physiology & Behavior 100 (2010) 549–559
both AGB [93,94] and VGB [92,95,96], have been widely observed, but
several studies have noted no change following either procedure [97–
100], and two cross-sectional studies found a reduction in ghrelin
concentrations following AGB, in comparison to BMI-matched counter-
Prospective and cross-sectional studies of ghrelin levels following
RYGB have produced mixed results, with the majority showing a
decrease in plasma ghrelin levels post bypass surgery [93,96,103,104].
Cummings et al.  in a cross-sectional study showed that ghrelin
levels were considerably reduced after RYGB relative to both obese
and normal weight controls. Higher levels of ghrelin were also
measured in obese persons who had lost weight by dieting than prior
to the diet , implicating a putative role for ghrelin in the adaptive
response that limits the weight loss by dieting and enhances the
likelihood of weight regain. Several researchers have since reported
significantly lower levels of ghrelin in surgical patients who lost
weight from RYGB in both cross-sectional and prospective studies
[100,103,105,106]. The first few months following BPD also resulted
in a significant reduction in ghrelin concentrations [100,101]. A post-
surgical reduction of ghrelin may contribute to the persistent weight
loss reported in obese patients following gastric bypass and mixed
malabsorptive procedures. However, a number of studies demon-
strated no significant change in ghrelin levels following gastric bypass
[97,107] and BPD , or even higher ghrelin concentrations
following both RYGB [109–111] and BPD [112–114].
Discrepancies among these results may be partially attributed to
variation in the types of surgical and control groups chosen. In a
prospective study, Faraj et al.  showed increased ghrelin
concentrations in post-RYGB surgical patients undergoing weight
loss butdid notincludeacontrolgroup.Despitetheincreasein ghrelin
levels observed in the surgical patients, they were still lower than
levels reported in normal weight or comparably obese participants
from other studies [11,116]. Similarly, another group found an
increase in ghrelin at 12 months following gastric bypass that was
comparable to BMI-matched controls . A rise in ghrelin may have
been anticipated following significant weight loss in these RYGB
patients; however, if the postsurgical cohort were compared to BMI-
matched controls that had lost weight conventionally, one might have
expected a relatively lower ghrelin level in the operative patients.
Variation in surgical technique and hormonal assays may also be
contributing factors in the differences reported in the literature.
Thaler and Cummings  proposed that the inconsistencies across
findings may be related to the integrity of autonomic vagal
innervation. Vagal innervation influences ghrelin levels [14,82,119],
and the degree to which the innervation is preserved is likely to differ
between surgeons. In addition, the accuracy of commercial ghrelin
assays used in the vast majority of studies has been raised .
Although it is not clear what the source of the variance is among
studies, the type of surgical procedure seems to have a major
influence on ghrelin levels. The overall reduction in postsurgical
ghrelin levels in gastric bypass may contribute to the greater weight
loss relative to other procedures, such as AGB [11,120].
Changes in PYY levels following bariatric surgery are under further
investigation, and although inconsistencies still remain, the majority
of evidence to date show that both restrictive [121–123] and
malabsorptive [97,105,124] operations lead to a rise in fasting and
postprandial PYY. Basal and postprandial PYY levels in morbidly obese
surgical patients after VGB, were similar to non-obese participants in
cross-sectional studies at 6 months, and were reasonably stable at
12 months post-surgery . Comparable postprandial PYY3–36
levels were also observed in post AGB patients and lean controls in
two studies [102,125]. Korner et al.  showed an early
postprandial rise in PYY concentrations in 12 patients in a cross-
sectional study at 15–17 months post-RYGB. Garcia-Fuentes et al.
reported that BPD produced a more substantial rise in PYY levels than
RYGB in 29 morbidly obese patients . Following RYGB, increases
in postprandial PYY have been reported [88,127] and may be due to
the absence of a functional pylorus and/or a significant portion of the
stomach and pylorus being bypassed resulting in a faster emptying
rate into small bowel. Higher PYY concentrations may lead to an early
sense of satiety and reduced meal size, and together with reduced
ghrelin may contribute to weight loss [88,128]. PYY inhibits ghrelin-
sensitive neurons in the arcuate nucleus of the hypothalamus in a
dose-dependent manner . A change in the PYY to ghrelin ratio
supporting PYY's anorectic action after bariatric surgery may result in
deactivation of appetite centers centrally regulated by ghrelin.
Longitudinal neuroimaging studies are needed to examine changes
within the same individual pre and post-surgery and across different
operations to clarify these points further.
Studies of post-operative changes in GLP-1 suggest that malab-
sorptive operations lead to a rise in fasting and postprandial GLP-1
concentrations [97,124,130–132]. Two studies have reported no
postsurgical change in GLP-1 following AGB [97,98]. In contrast
Reinehr et al.  reported lower GLP-1 levels in AGB patients at two
years post-surgery. On the other hand, an increase in GLP-1 has been
reported in one study  following SG. GLP-1 levels during an oral
glucose tolerance test were increased in VBG and BPD, with a greater
increase in BPD relative to VBG . GLP-1 is produced from the
distal small intestine; therefore a reduction in stomach size would not
be expected to affect circulating levels of GLP-1.
Findings regarding changes in fasting GLP-1 levels after RYGB
surgery are also mixed [121,127], but most report higher postprandial
levels post-surgery in RYGB [97,105,131,133]. In one study, significant
increases in GLP-1 levels were found six weeks following RYGB, when
Fig. 3. Illustrations of malabsorptive procedures. Reproduced with permission from Dr. Edward C Mun  A. Jejunoileal bypass; B. Biliopancreatic diversion; C. Biliopancreatic
diversion with duodenal switch.
C.N. Ochner et al. / Physiology & Behavior 100 (2010) 549–559
patients were still severely obese . Elevated levels of GLP-1 may
contribute to the sustained efficacy of RYGB as well as improve and
resolve diabetes, consistent with the incretin effect on weight and
glucose metabolism . RYGB restricts the stomach and bypasses
the duodenum, which facilitates the rapid delivery of food contents
through the GI tract, augmenting the release of GLP-1. It has been
hypothesized that the increase in hypothalamic satiety signals (e.g.
from GLP-1) may play contribute to the postsurgical weight loss
observed after malabsorptive procedures [124,135].
Conflicting postsurgical changes in CCK have also been found in
both restrictive and malabsorptive bariatric operations. Kellum et al.
 measured CCK levels after a glucose or protein meal before and
after RYBG and VBG, and the CCK response was not altered by either
intervention. However in another study, Foschi at al.  evaluated
patients before and after VBG surgery with healthy lean volunteer
controls and showed that post-VBG patients had a more significant
peak CCK response to an acidified meal known to enhance CCK
production  and a faster time to the peak than controls, without
differencesbetweenbaseline CCKconcentrations . Whilea decline
in CCK following RYGB might be predicted due to the diversion of
ingested food contents away from the duodenum, the jejunum also
secretes CCK . In rats, CCK was not significantly altered after
RYGB-induced weight loss . CCK is primarily important for short
termcontrolof appetiteandsatiety  andunlike leptinand insulin
, CCK does not appear to have an autonomous role in the long-
term regulation of energy balance and body weight . CCK can
work synergistically with leptin to promote short term reduction of
food intake in mice . More research is needed to determine CCK's
role in human obesity and the changes following bariatric surgery.
Several studies have demonstrated a significant decline in plasma
leptin levels after bariatric surgery in relation to fat loss, irrespective
of the surgical intervention [92,97,100,110]. A reduction in postpran-
dial leptin levels were found in post VBG surgical patients in
comparison to the baseline pre-operative state . Lower leptin
concentrations were seen at 2 and 12 months post BPD as compared
to pre-surgical levels . Serum leptin concentrations were also
reduced in morbidly obese patients that underwent BPD-DS
[144,145]. Rubino et al.  measured reduced leptin levels in
post-RYGB patients as compared to non-surgical weight loss controls.
Recent evidence suggests that leptin replacement therapy may aid in
weight loss maintenance .
The impact of bariatric surgery on insulin levels and insulin
resistance in obese persons is profound. In the bulk of restrictive
bariatric operations, insulin tends to fall in postsurgical obese patients
[92,97,100,110]. Reduced insulin concentrations were maintained at
two years post GB and VBG . Obese patients had decreased insulin
levels after LAGB than BMI-matched controls . Weight loss,
resulting from gastric bypass and BPD, improves insulin resistance
lowered and improved respectively in post-operative obese patients
with and without Night Eating Syndrome five months after RYGB
. Metabolic operations are being further investigated as an
alternative to pharmacological agents in the treatment of diabetes.
See Table 1 for a brief summary of changes in major appetite-related
peptides secondary to RYGB surgery.
6. Alterations in neural activation through weight loss and
The majority of studies in this area are cross-sectional (e.g., lean vs.
obese) and show differences in brain activation that suggest obese
individuals may experience greater reward-related (predominantly
mesolimbic) activation in response to appetitive stimuli [151–153]
and food intake (e.g. [68,154]). There is, however, controversy
surrounding this hypothesis  and it remains unknown whether
any such lean vs. obese differences are cause or consequence of an
obese state, as very few longitudinal studies have been conducted.
Despite radical postsurgical alterations in gut peptide signaling and
established interactions between gut peptides and the neural control
of food intake, there has been only one study of changes in brain
receptor site binding  and one investigation of changes in
neurological responses to food stimuli following bariatric surgery
. The limited available studies of the effect of weight loss and
bariatric surgery on brain activation discussed below may provide
insight and hypotheses for future investigations.
Althoughcross-sectional, comparisons betweenobeseandweight-
suppressed individuals, who may be prone to weight gain [157,158],
may provide some insight into the association between weight loss
and neural activation in response to appetitive stimuli and/or food
intake. Cornier et al.  found greater hypothalamic activation in
response to palatable food cues in lean individuals after a controlled
five-day eucaloric diet relative to after 2 days of 30% overfeeding,
suggesting an association between energy stores and hypothalamic
activity in response to appetitive cues. This may reflect down-
regulation of hypothalamic activity in lean individuals in response to
appetitive cues upon entering a state of positive energy balance.
Reduced obese (obesity-prone) individuals, however, did not show
the same attenuation of hypothalamic response to food cues as lean
individuals upon entering the same overfed state, suggesting an
impaired interaction between appetitive stimuli and the homeostatic
regulation of energy intake . Although speculative, the absence
of a decrease in hypothalamic activation in response to appetitive
stimuli upon entering an overfed state may contribute to more or
sooner resumption of ‘homeostatic-based’ eating . In addition,
impaired attenuation of hypothalamic activity may also leave open
the potential for hypothalamic up-regulation of reward-related
activation [53,54], which may be consistent with evidence showing
greater PFC activation in reduced-obese relative to lean individuals
. Although almost certainly an oversimplification, as different
subregions within both the hypothalamus  and PFC [72,162] play
differentroles in the regulationof energyintake, this blunt framework
may help formulate testable hypotheses regarding the interaction
between homeostatic (hypothalamic) and hedonic systems in appeti-
Other studies have directly assessed acute responses to food intake,
which yield different conclusions than those proposed by Cornier and
colleagues [159,160] who examined neural responses to appetitive
stimuli, potentially reflecting differences between anticipated and
consummatory reward processing . For example, Del Parigi et al.
 showed differences in reward-related activation in response to a
meal between lean and obese participants but no differences between
obese and formerly obese participants. The authors suggest that
differential or “abnormal” neural responses to meal ingestion in obese
a cross-sectional reanalysis of existing data, Le et al. , reported that
formerly obese women who successfully achieved weight loss by diet
and exercise and maintained their weightloss for 3 monthshad greater
activation of the dorsolateral prefrontal cortex (dlPFC) in response to a
meal than did obese women. The authors hypothesize that this
difference is related to greater inhibitory or satiety-related activation,
that the increased dlPFC activation reflects greater reward processing
In the only available longitudinal study of brain activation pre and
post non-surgical weight loss, Rosenbaum et al.  reported changes
in brain activation in response to food cues following non-surgical
weight loss (10% initial body weight) in 6 obese men and women.
Following weight loss, leptin-reversible increases in activation were
seen in the brainstem, parahippocampal gyrus, culmen, parahippo-
campal gyrus, inferior and middle frontal gyri, middle temporal gyrus,
and lingual gyrus, while leptin-reversible reductions in activation
were observed in the hypothalamus, cingulate gyrus, and middle
C.N. Ochner et al. / Physiology & Behavior 100 (2010) 549–559
frontal gyrus. Based on these results, the authors suggest that some
changes in neural processing that may be associated with hunger and
subsequent weight (re)gain may be leptin-reversible . However,
the complexity of these findings also illustrate the need for further
controlled, hypothesis-driven research of brain activation in response
to weight change before conclusions can be drawn about the
interaction between brain systems (homeostatic vs. hedonic activa-
tion, weight change (gain vs. loss) and state of energy balance
(positive vs. negative) in responses to appetitive stimuli.
Finally, two recent studies have examined the effect of bariatric
surgery on neural activity. Using PET, Steele et al.  recently
examined dopamine D2 receptor activity in five obese female subjects
pre and six weeks after laparoscopic RYGB surgery. Five regions of
interest were studied (ventral striatum, anterior and posterior
putamen, anterior and posterior caudate nucleus) and the researchers
found that while baseline D2 binding in RYGB patients did not differ
from non-obese controls, D2 receptor availability increased from pre
to post-surgery, with the increase in receptor availability roughly
proportional to the amount of weight lost. This suggests that the
correction of diminished D2 binding in obese subjects (due to D2
receptor down-regulation) may play a role in appetite suppression
and weight loss after RYGB.
The current authors used fMRI to investigate whether laparoscopic
RYGB would result in significant changes in brain activation in
response to high- and low-calorie food stimuli in 10 female patients.
Givenconsistentpostsurgical reductionsin the desireforand intakeof
Fig. 4. Glass brain figure depicting brain activation in response to high-calorie relative to low-calorie food stimuli (high-calorie–low-calorie contrast) at pb0.05 uncorrected. A
greater difference between mesolimbic dopaminergic pathway activation in response to high-calorie foods and mesolimbic dopaminergic pathway activation in response to low-
calorie foods can be seen pre-relative to post-surgery. For display purposes, activation maps are shown without a cluster extent threshold.
Fig. 5. Coronal and sagittal slices depicting areas in which the difference between activation in response to high- and low-ED foods (High-ED–Low-ED Contrast) was greater pre-
relative to post-surgery. Activation was considered significant at pb0.05 uncorrected, with an applied cluster extent threshold (k=22). The largest clusters (kN80) were seen in the
dlPFC (y=42; top and cluster), ventrolateral PFC (vlPFC; y=42; bottom cluster), ventral striatum (y=4; bottom two clusters), putamen and lentiform nucleus (y=0; bottom
cluster), and dmPFC (x=4; rightmost cluster). A nonsignificant cluster (k=20) was also observed in the VTA (x=4; white arrow). MNI coordinates are given in upper left corner of
each panel. The color bar represents t values.
C.N. Ochner et al. / Physiology & Behavior 100 (2010) 549–559
food [158,159], it was hypothesized that participants undergoing
RYGB would show postsurgical reductions in mesolimbic reward
pathway activation in response to food cues. It was also anticipated
that postsurgical reductions in mesolimbic activity and desire to eat
would be greater in response to high-ED relative to low-ED food cues
given that presurgical preferences for foods high (vs. low) in fat and
calories are typically reduced or eliminated following RYGB surgery
[84,86]. Results revealed postsurgical reductions in brain activation in
key areas within the mesolimbic reward pathway in response to food
cues, which were significantly more pronounced in response to food
cues that were high (vs. low) in caloric density (Figs. 4 and 5). These
changes mirrored concurrent postsurgical reductions desire to eat
following exposure to food cues that were high (vs. low) in caloric
density (Fig. 6). These findings support the contention that RYGB
surgery leads to substantial changes in neural responses to food cues
encountered in the environment, provide a potential mechanism for
the selective reduction in preferences for high-calorie foods, and
suggest partial neural mediation of changes in caloric intake seen
following RYGB surgery.
Obesity is linked to significant abnormalities in the neurohormonal
of gut peptides and brain activation in animals and humans. Yet there
remains much work to be done in linking gut peptide and brain
functions, particularly as they relate to energy balance. Although
replication is needed, recent findings suggest that reward-related
brain activation caused by exposure to appetizing food cues may be
attenuated by elevations in PYY3–36and GLP-1, simulating a postpran-
dial (fed) state [71,73]. In theory, these postprandial satiety signals are
received by the hypothalamus , in turn down-regulating hedonic
activation in the brain and reducing the likelihood or volume of
subsequent food intake via reductions in perceived reward value .
However, despite putative attempts by the ‘homeostatic’ system to
maintain energy balance, there is substantial evidence (particularly in
obese individuals) to suggest that the hedonic system can override the
homeostatic system and drive food intake even when sated if the
perceived reward value is sufficiently high [41,61].
Surgical interventions for obesity, particularly RYGB, may lead to
substantial and simultaneous changes in gut peptides , brain
activation [155,156], desire to eat  and taste preferences .
Thus, the effects of bariatric surgery on the neurohormonal regulation
of energy intake provides a tantalizing ‘natural’ experiment with
which to explore gut–brain interactions [165,166], with an increasing
number of studies suggesting that postsurgical changes within the
neurohormonal system may account for a proportion of postsurgical
weight loss [8,167]. For example, postsurgical reductions in ghrelin
and earlier and enhanced postprandial elevations of PYY and GLP-1
may reduce hunger and promote satiety . The success of
combination, relative to purely restrictive, procedures suggests that
hormonal alterations may contribute to weight loss . Relative to
changes in gut peptides, very little is known about changes in brain
activation following bariatric procedures. Investigations of non-
surgical weight loss support an increase in reward-related/hedonic
activation in response to appetitive cues [68,72,154,163], which could
help explain weight regain in dieters. In contrast, the absence of an
increase in desire to eat following RYGB, even on exposure to highly
palatable food cues [84,122], is striking, and consistent with systemic
changes in neural responses to food cues.
Interactions between postsurgical changes in gut peptides and
neural activity have been widely proposed, but remain to be explicitly
tested. Investigations of neurohormonal changes in RYGB may assist
in developing non-surgical interventions to treat obesity and related
comorbidities, which could serve as a viable treatment alternative for
obese individuals who do not have access or do not qualify for
bariatric surgery. Pharmacological activation of the hedonic network
in animals, already fed beyond satiety, produces hyperphagia and
preferentially increases the intake of foods high in fat and sugar
[169,170]. Thus, identifying the actions of RYGB on gut–brain
signaling may make it possible to develop pharmacological agents
to increase satiety, and reduce hunger and preferences for high-ED
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