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Physiological Mechanisms Behind Roux-En-Y Gastric Bypass Surgery
Physiological Mechanisms Behind Roux-En-Y Gastric Bypass Surgery
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University of Zurich
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CH-8057 Zurich
www.zora.uzh.ch
Year: 2014
Abstract: Obesity and its related comorbidities can be detrimental for the affected individual and chal-
lenge public health systems worldwide. Currently, the only available treatment options leading to clini-
cally significant and maintained body weight loss and reduction in obesity-related morbidity and mortality
are based on surgical interventions. Apart from the ’gold standard’ Roux-en-Y gastric bypass (RYGB),
the vertical sleeve gastrectomy and gastric banding are two frequently performed procedures. This review
will discuss animal experiments designed to understand the underlying mechanisms of body weight loss
after bariatric surgery. While caloric malabsorption and mechanical restriction are no major factors in
this respect, alterations in gut hormone levels are invariably found after RYGB. However, their causal
role in RYGB effects on eating and body weight has recently been challenged. Other potential factors
contributing to the RYGB effects include increased bile acid concentrations and an altered composition
of gut microbiota. RYGB is further associated with remarkable changes in the preference for different
dietary components such as a decrease in the preference for high fat or sugar; it is important to note that
the contribution of altered food preferences to the RYGB effects on body weight is not clear.
DOI: https://doi.org/10.1159/000354319
Key Words high fat or sugar; it is important to note that the contribution
Roux-en-Y gastric bypass · Vertical sleeve gastrectomy · of altered food preferences to the RYGB effects on body
Gut hormones · Restriction · Malabsorption · Energy weight is not clear. © 2014 S. Karger AG, Basel
expenditure
Abstract Introduction
Obesity and its related comorbidities can be detrimental for
the affected individual and challenge public health systems The obesity epidemic and its related comorbidities con-
worldwide. Currently, the only available treatment options stitute a major challenge for both personal health and pub-
leading to clinically significant and maintained body weight lic health systems worldwide. The enormous increase in
loss and reduction in obesity-related morbidity and mortal- the knowledge about the physiological mechanisms con-
ity are based on surgical interventions. Apart from the ‘gold trolling eating and body weight contrasts with the lack of
standard’ Roux-en-Y gastric bypass (RYGB), the vertical available pharmacology-based therapies that lead to safe,
sleeve gastrectomy and gastric banding are two frequently efficient and long-lasting body weight reductions and an
performed procedures. This review will discuss animal ex- ensuing reduction in obesity-related comorbidities. Re-
periments designed to understand the underlying mecha- cent insights into underlying mechanisms of obesity and
nisms of body weight loss after bariatric surgery. While ca- bariatric surgery have led to promising perspectives with
loric malabsorption and mechanical restriction are no major respect to gut hormone-based strategies against obesity.
factors in this respect, alterations in gut hormone levels are However, the best results for maintained weight reduction
invariably found after RYGB. However, their causal role in and improvement of comorbidities are still achieved by
RYGB effects on eating and body weight has recently been bariatric surgery [1–4]. This review aims to summarize key
challenged. Other potential factors contributing to the RYGB findings with respect to underlying physiological mecha-
effects include increased bile acid concentrations and an al- nisms of the Roux-en-Y gastric bypass (RYGB) procedure
tered composition of gut microbiota. RYGB is further associ- which by many is still considered the gold standard in bar-
ated with remarkable changes in the preference for different iatric surgery. Reference will also be made to vertical sleeve
dietary components such as a decrease in the preference for gastrectomy (VSG) and to gastric banding (GB).
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E-Mail karger@karger.com
CH–8057 Zurich (Switzerland)
www.karger.com/dsu
E-Mail tomlutz @ vetphys.uzh.ch
Color version available online
Gastric pouch
Alimentary limb
Biliopancreatic
limb
Common channel
Fig. 1. Schematic representation of the sham operation (left), the RYGB (middle) and the VSG (right) in rats. In
our laboratory, the different segments of the small intestine after the RYGB operation in rats have the following
approximate dimensions: biliopancreatic limb 10 cm (green/light grey); alimentary limb (Roux limb) 50 cm (red/
middle grey); common channel 25 cm (blue/dark grey). The gastric pouch has a volume of <5% of the intact
stomach.
Research with animal models helped to elucidate some Effects of RYGB on Body Weight
of the physiological mechanisms that potentially underlie
the treatment success of bariatric surgery. Figure 1 illus- RYGB in rats or mice leads to a rapid and marked de-
trates schematically the pre- and postoperative anatomy crease in body weight compared to sham-operated ani-
of the gastrointestinal tract after RYGB and VSG opera- mals [e.g. 5–7]. RYGB-operated rats typically lose about
tions in rats. Both operations reduce eating at least tem- 20% of their presurgical body weight which then plateaus
porarily and may increase energy expenditure. Both pro- at a constant level; in some studies, body weight is slowly
cedures further lead to changes in food preferences. The regained over time, but without ever reaching the body
majority of data collected with the help of preclinical weight of respective control animals. A decrease in body
studies seem to be consistent with findings in humans. fat mass largely accounts for the decrease in body weight,
However, increases in energy expenditure after RYGB while lean body mass is typically preserved.
seem to be less consistent in humans when compared to Theoretically, body weight loss after RYGB in com-
most animal models; this may be related to the much larg- parison to sham-operated controls can be explained by
er heterogeneity of study populations in humans com- reduced calorie intake, increased energy expenditure, re-
pared to laboratory animals. duced nutrient availability (e.g. caloric malabsorption),
Current research often focuses on altered concentra- altered metabolic efficiency or by a combination of all
tions of gut hormones like glucagon-like peptide-1 (GLP- these factors. Considering the available literature, re-
1) or peptide YY (PYY) and metabolites that per se are duced eating and increased energy expenditure may play
known to affect eating and to modulate nutrient metabo- a much greater role after RYGB surgery than caloric mal-
lism. It needs to be pointed out, however, that association absorption which seems to be only of minor importance
and causality must not be confounded because measur- for the observed effects of RYGB [5, 8]. Thus, even
able changes in circulating parameters after bariatric sur- though the gastrointestinal anatomy is significantly re-
gery do not necessarily play a causal role in the observed arranged after RYGB and even though the stomach, du-
effects of bariatric surgery; hence, it is not yet clear wheth- odenum and proximal jejunum are excluded from the
er these changes are necessary or sufficient for reduced flow of ingested food, it seems that the total digestive and
eating or body weight. absorptive capacity of the small bowel still suffices to
avoid maldigestion and subsequent caloric malabsorp-
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480
460 Effect of RYGB on Food Intake and Meal Pattern
440
420 One important factor that contributes to body weight
400 loss after RYGB is a reduction in overall food intake; the
380 reduction in eating seems to be a voluntary process since
360 studies in humans have shown that pre-meal hunger is
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 not higher and post-meal satiation is not lower after
Time (days)
RYGB despite an overall lower food intake [12, 13]. In
most published studies, RYGB leads to a significant re-
duction in eating compared to ad libitum-fed sham-op-
Fig. 2. Development of body weight from the day of operation (day
0) in sham-operated rats (squares) and RYGB rats (blue/grey cir- erated rats. RYGB rats typically eat less during the dark
cles). On day 7 after surgery, sham-operated rats were randomized phase of the light/dark cycle and during an entire 24-hour
to be fed ad libitum (white squares; average daily food intake ap- period; interestingly, light-phase food intake is increased
prox. 35 g), pair fed to the RYGB rats (red/dark grey squares; aver- in at least some studies (see also fig. 3) [5].
age daily food intake approx. 25 g) or food restricted to match the The reduction in overall food intake is accompanied
rats’ body weight to that of RYGB rats (green/light grey squares;
average daily food intake approx. 8 g). Of note, from about 3 weeks by a typical change in meal pattern [5, 6, 14]. Interest-
after surgery, body weight-matched rats received on average about ingly, meal pattern changes in rodent models of RYGB
50% of the amount of food eaten by the ad libitum-fed rats to main- resemble those seen in RYGB patients. Both, patients and
tain the same body weight as RYGB rats. Data are shown as mean rats seem to eat and drink less and on average ingest
± SEM with n = 6–8 per group. smaller meals that are consumed with slower eating rates
after RYGB surgery. Simultaneously, the meal frequency
increases after RYGB, which however does not compen-
sate for the reduced meal size. Similarities in meal pat-
tion. This may at least partly be due to the massive hy- terns between humans and rats after RYGB suggest that
pertrophy of the small bowel that is observed predomi- the physiological effects of RYGB may rather rely on al-
nantly in those gut segments that are still in contact with tered feedback signals from the gastrointestinal tract to
nutrients (i.e. alimentary limb and common channel; see control centers of eating in the brain than on (confound-
fig. 1) [5, 9, 10]. It must be noted, however, that the con- ing) psychosocial influences, including dietary counsel-
tribution of malabsorption to the RYGB-induced body ing.
weight loss may increase if animals are maintained on a Interestingly, RYGB rats consume smaller meals in the
high-fat diet [11]. Similarly, in our own laboratory, tem- dark phase, but larger meals in the light phase when com-
porary malabsorption may occasionally be observed un- pared to sham-operated control rats. As a result, RYGB
der conditions of high fat feeding (e.g. 60% fat by calo- rats have approximately the same meal size during the
ries), but the contribution to body weight loss seemed to dark and light phase while sham-operated rats consume
be minor. significantly more food per meal during the dark phase
Figure 2 indicates that reduced eating is one, but clear- than during the light phase. Furthermore, RYGB rats
ly not the only factor contributing to body weight reduc- consume significantly more meals during 24 h than
tion after RYGB in rats. RYGB rats spontaneously eat less sham-operated rats (fig. 3).
after surgery when compared to sham-operated controls; At first sight, one could argue that an overall increase
however, sham-operated rats that are pair fed to RYGB in meal frequency together with a constant meal size in-
rats have a greater body weight than ad libitum-fed RYGB dicate the inability of RYGB rats to overcome a mechani-
rats. Only if sham-operated rats undergo more severe cal constraint executed by a small gastric pouch; in other
food restriction and get less food offered than RYGB rats, words, these compensatory mechanisms may be neces-
do they show a body weight trajectory that is comparable sary to overcome mechanical restriction in order to
to RYGB rats. As caloric malabsorption has been shown achieve an acceptable level of total caloric intake. Several
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Number of meals
15
or during an entire 24-hour period, respec- *** **
3
tively; during the light phase, meal size 10
slightly increases but meal number does 2
not change. Meal pattern analysis was per-
**
5
formed 6–8 weeks postoperatively. Data 1
are shown as mean ± SEM with n = 6–8 per
group. * p < 0.05, ** p < 0.01, *** p < 0.001, 0 0
Dark phase Light phase 24 h Dark phase Light phase 24 h
significant difference between sham-oper-
ated and RYGB rats.
important findings argue against this interpretation. tern after RYGB, but also VSG, because there does not
Firstly, both humans and rats do not increase their water seem to be a ceiling effect at the typical level of ad libitum
intake with the meal, suggesting that there is no attempt food intake after RYGB or VSG.
to overcome mechanical constraint through food dilu-
tion with water. Secondly, there is no correlation between
the size of the gastrojejunal anastomosis and weight loss RYGB Changes the Gut Morphology in Specific Gut
in RYGB rats [15]. Thirdly, blocking the pleiotropic gut Segments
hormone response in humans after RYGB with a so-
matostatin analogue (which does not change the size of The RYGB procedure is associated with typical chang-
the gastric pouch or stoma) can almost double ad libitum es in the morphology of intestinal mucosa [e.g. 5, 9, 10,
food intake [12]; similar effects are seen in rats [16]. Fur- 19]. This has most consistently been described in RYGB
ther, if mechanical restriction were a major factor, one rats, and the phenomenon seems to be less marked in
would assume that RYGB animals are more hungry than RYGB mice. In rats, the total length of the small intestine
sham-operated animals and try to ingest calorically dense remains unaltered, but a marked increase in wet weight
food to overcome the volume restriction; however, the of the small intestine indicates segmental hypertrophy af-
exact opposite is the case because RYGB reduces high-fat ter RYGB. Specifically, muscular and mucosal layers are
diet intake relative to low fat intake [e.g. 6, 17]. Finally, if significantly thicker in the alimentary (Roux) limb after
mechanical constraint were an important factor, then it RYGB in comparison with corresponding intestinal seg-
should be impossible to exceed the maximal limit. Thus, ments in sham-operated controls; both mucosal crypt
we food restricted a group of RYGB rats such that they depth and villi height increased. Depending on the di-
received less than half of their ad libitum food intake over mensions of the various limbs after RYGB [5, 9, 10], sim-
about 2 weeks with subsequent unlimited access to solid, ilar changes may also be observed in the common channel
normal chow; RYGB rats increased their food intake as of some RYGB models, but not in the biliopancreatic
soon as ad libitum food was available. Instead of return- limb.
ing to the level of food intake seen in the ad libitum-fed The underlying mechanisms leading to hypertrophy of
RYGB rats, the food-restricted RYGB rats ate significant- the intestinal mucosa including muscle layers remain un-
ly more and food intake even exceeded that of sham-op- known. Mechanical or chemical factors or a combination
erated ad libitum-fed rats (fig. 4). Similarly, Stefater et al. of both may be involved. It is however intriguing that not
[18] have shown that temporary restriction of food access all intestinal segments show a hypertrophic response.
lowers body weight in VSG and control animals; when One possible explanation is linked to an increased release
returning to an ad libitum feeding regimen, all animals, of GLP-2 from intestinal L-cells [19] (see also below) fa-
including the VSG rats, overate to compensate for the re- cilitating intestinal hypertrophy in conjunction with in-
striction period and reached their pre-restriction body traluminal factors such as stimulation by nutrients. Over-
weight in a similar time frame. Overall, these data indi- all, it may be postulated that hypertrophy of certain intes-
cate that it appears unlikely that mechanical constraint is tinal segments in RYGB animals represents an adaptive
a major factor of reduced eating and the altered meal pat- response to optimize nutrient digestion and absorption
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400 20 20
300 10 10
200 0 0
0 5 10 15 20 25 30 35 40 45 50
a Postoperative days b c
Fig. 4. a Body weight in rats that were sham operated (white from day 15 to 30 (sham: white bar; RYGB ad libitum: black bar;
squares) or RYGB operated (grey and black squares) on day 0. Be- RYGB restricted: grey bar). From day 30, all rats had again ad libi-
tween postoperative days 15 and 30, part of the RYGB rats (grey tum access to food. c Average daily food intake between days 30
squares) were food restricted to 50% of the food eaten by the ad and 50. Data are shown as mean ± SEM with n = 6–8 per group.
libitum-fed RYGB rats (black squares). b Average daily food intake * p < 0.05, *** p < 0.001.
under conditions where nutrients and digestive juices monal secretory capacity of the small intestine increases
from the pancreas and liver mix more distally than under after RYGB. Further, L-cell density seems to increase
physiological conditions. Similar responses can be seen in along the rostrocaudal axis. Importantly, however, it
experiments where segments of the small intestine have must be noted that the majority of the total number of L-
been surgically removed. cells is found in more proximal gut segments, and not in
Because of the potential importance of gut hormones the ileum, after RYGB surgery in rats [20].
for the beneficial effects of RYGB and other types of bar-
iatric surgery, several groups also investigated whether
RYGB modifies the distribution or density of enteroen- RYGB Surgery Changes the Concentration of
docrine cells in the gastrointestinal tract. Consistent with Circulating Gut Hormones
the general hypertrophy of the intestinal mucosa, there
are clear indications for an adaptive increase in the num- One of the most consistent findings and one of the
ber of endocrine cells. This translates into an increase in most frequently proposed mechanisms contributing to
the absolute number of L-cells releasing GLP-1, GLP-2 reduced eating and body weight after RYGB surgery is the
and PYY, and of cholecystokinin (CCK) immunoreactive increased secretion of gut hormones, in particular the L-
cells; while major effects were seen in the alimentary limb cell products GLP-1 and PYY, but also amylin and CCK
and the common channel, no changes were observed in [12, 13, 19, 21, 22]. The single or combined action of these
the biliopancreatic limb. Interestingly, however, regional satiating hormones provides a plausible explanation for
density of enteroendocrine cells remains unaltered [9, the decrease in meal size observed in RYGB rats. The
20]. blood concentration of ghrelin, in contrast, seems to de-
When testing the specific expression of preprogluca- crease after RYGB, which theoretically could be associ-
gon (for GLP-1) and PYY in the intestinal segments, the ated with a reduced drive to eat; however, data about
mRNA expression per cell is only increased in the com- changes in circulating ghrelin are rather inconsistent [13,
mon channel, but not in the alimentary limb [20]; hence, 21, 23, 24] and the relevance of changes in ghrelin secre-
it seems that both the (general) stimulus that leads to in- tion, if they occur, is also unclear. Further, it is unclear
testinal hypertrophy (perhaps induced by increased GLP- whether the observed changes in ghrelin concentrations
2 secretions) and the presence of nutrients plus bile acids, observed in some studies are physiologically relevant
gastric and pancreatic juices may be necessary to increase modulators of eating; finally, ghrelin-deficient mice
gastrointestinal hormone production at the level of indi- showed an unaltered body weight-lowering response to
vidual cells. Overall, data clearly indicate that the hor- the VSG procedure [25].
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Chow
is necessary for beneficial effects of RYGB (or other bar-
15 iatric surgery procedures, respectively) [2, 3, 43] on insu-
lin sensitivity and whole-body energy metabolism.
10
5
Changes in Energy Expenditure after RYGB Surgery
0
References 1 Rubino F, Kaplan LM, Schauer PR, Cum- 3 Schauer PR, Kashyap SR, Wolski K, et al: Bar-
mings DE: The Diabetes Surgery Summit iatric surgery versus intensive medical thera-
consensus conference: recommendations for py in obese patients with diabetes. N Engl J
the evaluation and use of gastrointestinal sur- Med 2012;366:1567–1576.
gery to treat type 2 diabetes mellitus. Ann 4 Mingrone G, Panunzi S, De Gaetano A, et al:
Surg 2010;251:399–405. Bariatric surgery versus conventional medical
2 Rubino F, Schauer PR, Kaplan LM, Cum- therapy for type 2 diabetes. N Engl J Med
mings DE: Metabolic surgery to treat type 2 2012;366:1577–1585.
diabetes: clinical outcomes and mechanisms 5 Bueter M, Lowenstein C, Olbers T, et al: Gas-
of action. Annu Rev Med 2010;61:393–411. tric bypass increases energy expenditure in
rats. Gastroenterology 2010;138:1845–1853.
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