Changes in Gut Hormones After Bariatric Surgery

R. P. Vincent; C. W. le Roux

Disclosures

Clin Endocrinol. 2008;69(2):173-179. 

In This Article

Gut Hormones

The gut–brain axis is a major component of appetite regulation. The gut hormones have either anorexigenic or orexigenic action on food intake and it is now evident that these gut hormone secretions are altered following bariatric surgery. The hormones reviewed here are ghrelin, peptide YY (PYY), glucagon-like peptide 1 (GLP-1), oxyntomodulin (OXM), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK) and pancreatic polypeptide (PP).

Ghrelin is a 28-amino acid acylated peptide and an orexigenic hormone.[9] It is released from the stomach and upper intestine preprandially and is rapidly suppressed by food intake,[9] in proportionate to the calorie ingestion.[10] Reductions in food intake and body weight have been reported among adult animals subjected to pharmacological blockade of ghrelin signalling, by administration of ghrelin-specific antibodies into the brain.[9] An increase in the plasma ghrelin level with diet-induced weight loss is consistent with the hypothesis that ghrelin has a role in the long-term regulation of body weight.[11] Interestingly obese individuals have lower fasting ghrelin levels, and demonstrate reduced postprandial ghrelin suppression compared to normal weight individuals.[12] The gene that encodes ghrelin has also been found to encode another peptide known as obestatin. Even though obestatin was initially thought to produce anorectic signals, the role of this peptide in the regulation of food intake is not clearly understood.

In rodent studies, chronic administration of ghrelin increased calorie intake and promoted weight gain.[13,14] On the other hand when ghrelin is pharmacologically inhibited it decreases food intake and weight.[15] A number of cross-sectional and prospective studies have demonstrated that basal ghrelin levels in obese subjects are lower than in lean subjects. There is, however, conflicting findings following RYGB, with studies demonstrating a reduction,[16,17] no change[18,19] or increased ghrelin levels.[20,21,22] After gastric restrictive surgery such as vertical banded gastroplasty (VBG) or GB, ghrelin levels increase. Korner etal. also demonstrated that maximal postprandial suppression of total ghrelin was blunted in the GB group compared with RYGB and that postprandial suppression of octanoylated ghrelin was also less in GB compared with RYGB.[23] The difference between these procedures may be the key to understanding how RYGB sustains weight loss compared with restrictive surgeries.[23,24,25] Paradoxically GB leads to an increase in fasting plasma ghrelin and is accompanied by a decrease in hunger, disinhibition of eating and an increase in cognitive restraint. Thus, changes in eating behaviour, which promote reduction of food intake and not fasting ghrelin, seems to determine weight loss achieved by GB.[26] An intact vagus nerve also has been shown to be required for ghrelin's appetite effect,[27] and whether this has any relevance after GB still needs to be determined. On the other hand one study showed that following RYGB, ghrelin levels fell during the first postoperative day, increased after 1month to preoperative levels and rose further at 6 and 12months. This transient suppression of ghrelin could possibly be due to vagal dysfunction and subsequently with weight loss ghrelin secretion increases to higher than preoperative levels.[28] A study on ghrelin concentration in obese patients prior to and 5days and 2months following BPD demonstrated that unlike after dieting or RYGB, only an initial reduction in ghrelin concentration was observed. However 2months following BPD, when food intake had nearly completely resumed the values returned to the preoperative levels.[29] This is consistent with the hypothesis that ghrelin production from the stomach is greatly influenced by the direct contact of ingested food with the gastric cells. This finding is, however, conflicting with evidence showing that small intestinal nutrient exposure is sufficient for food-induced plasma ghrelin suppression in humans and that gastric nutrient exposure is not necessary for its suppression.[30] Given the current data it is difficult to fully understand the mechanism involved in the release of ghrelin after bariatric surgery. The degree of hyperinsulinaemia is a known major determinant of ghrelin suppression amongst obese subjects.[31,32] Changes in ghrelin release following surgical weight loss might depend on the degree of preoperative insulin resistance and the degree to which insulin sensitivity is restored. The degree of vagal dysfunction following the surgical procedures may also contribute to the changes in the observed ghrelin levels.

PYY where Y depicts the abbreviation for tyrosine is a naturally occurring peptide, released into the circulation by intestinal endocrine L-cells of the distal gut following food ingestion along with GLP-1 and OXN. PYY together with NPY belongs to the PP family.[33] PYY is an endogenous Y2-receptor (Y2R) agonist, which also binds to the Y4 and Y5 receptors. PYY is released postprandially in proportion to the calories ingested,[34] however, the secretion of PYY is not altered by gastric distension.[35] It is known to inhibit gastric, pancreatic and intestinal secretion as well as gastrointestinal motility.[33,36] PYY3-36 is the major form of circulating PYY and binds to the hypothalamic NPY Y2R with a high-affinity, reducing food intake in rodents and humans.[37] PYY is hypothesized to inhibit food intake via activation of the auto-inhibitory presynaptic NPY Y2R present on the ARC NPY neurones.[38]

Previously GB was thought to work through restriction of food intake, BPD through calorie malabsorption and RYGB was a hybrid between restriction and calorie malabsorption. However these concepts are being challenged as there is limited data to support the role of malabsorption or restriction in weight loss.[39] Studies have also shown that following BPD and RYGB significant gut hypertrophy takes place thus reducing the chances of calorie malabsorption.[40,41] This is consistent with studies that have shown an increase in the satiety hormones PYY and GLP1 in the distal small intestine following bariatric surgical procedures which lead to increased satiety and reduced food intake. Compared with lean and obese controls, following RYGB, patients have increased postprandial plasma PYY and GLP-1 favouring enhanced satiety. Rodent models with jejuno-intestinal bypass (JIB), showed elevated PYY and GLP-1 compared to sham-operated rats. Also exogenous PYY reduces food intake and blockade of endogenous PYY increases food intake. Thus endocrine response may contribute to appetite reduction and long-term changes in body weight.[40] PYY was measured in the fasted state and in response to a liquid test meal in three groups of adult women: lean; weight-stable 35±5months after RYGB; mean BMI 33kg/m2 and matched to the surgical group for BMI and age. In response to the test meal, there was an early exaggerated rise in PYY in the RYGB group at 60min and the area under the curve was significantly greater compared with both control groups. This exaggerated postprandial PYY response after RYGB, may contribute to weight loss and to the ability of an individual to maintain weight loss after this procedure.[42] In another study; 12 morbidly obese patients had blood samples taken prior to surgery, and at 6 and 12months after VBG. On each occasion blood was collected in basal conditions of fasting and at 10, 15, 20, 30 and 60min after the ingestion of a semiliquid test meal. Six healthy non-obese subjects acted as controls. There was a significant difference between the preoperative PYY concentrations in obese patients compared to controls. However, there was no difference between the PYY concentrations in the obese patients after VBG and the controls. This demonstrates that PYY concentration is lower in obese patients compared with non-obese which after VBG, gradually rises to non-obese levels.[43] Another study included four groups of women: lean, GB, RYGB and controls matched for BMI to the surgical groups. Fasting total PYY and PYY3-36 were similar among all groups, but the postprandial response in the RYGB group was exaggerated such that, 30min after the meal total and PYY3-36 levels were two to fourfold greater compared with all other groups. This difference in postprandial concentrations of PYY between RYGB and GB subjects would be expected to promote increased satiety and earlier meal termination in RYGB and may aid in greater weight loss compared to GB.[23] Six patients were seen before and at 1, 3 and 6months post-RYGB. Blood was collected after a 12-h fast and at regular intervals after a mixed 420-kcal meal. At 1, 3 and 6months after RYGB, progressively increasing PYY and GLP-1 responses were observed. Postprandial satiety was significantly increased by 1month after surgery and this was maintained until the end of the study.[44] Once substantial weight loss was induced by RYGB, the PYY response to oral glucose tolerance test (OGTT) was significantly higher than in controls. PYY increased approximately 10-fold following OGTT and remained significantly higher than fasting levels for all subsequent time-points. In contrast, PYY levels in obese and lean controls increased to a peak of approximately twofold, which was only borderline significant.[44] Hence RYGB results in a more robust PYY response to caloric intake, which may contribute to the sustained efficacy of this procedure. These findings provide further evidence for a role of gut-derived hormones in mediating appetite changes after RYGB.[45] In a prospective study changes to GLP-1, PYY, hunger and satiety in response to a standardized test meal were tested in nine normal-glucose-tolerant obese subjects before and 6weeks after RYGB. Before surgery, meal ingestion failed to stimulate GLP-1 and PYY secretion. Six weeks after surgery, despite subjects still being markedly obese, the area under the curve of GLP-1 and of PYY in response to the standardized test meal was significantly elevated. These hormonal responses were significantly larger than those observed in a group matched for the BMI attained 6weeks after surgery. The area under the curve of GLP-1 and PYY were accompanied by a significant decrease in fasting and postprandial hunger and a significant increase in satiety after meal intake. However, a significant correlation between changes in the gut hormones and eating behaviour parameters was not found.[46] Another recent randomized double-blinded saline controlled study in a group of matched RYGB and GB subjects demonstrated that suppressing the gut hormones release with octreotide (a somatostatin analogue), increased food intake in the RYGB subjects by 87% but not in the GB patients. As endogenous gut hormone responses are exaggerated in RYGB, but not GB subjects this further suggests that gut hormones may play a role in food intake after RYGB.[47]

GLP-1 is released from the lower intestinal endocrine L-cells in response to ingested nutrients along with PYY and OXM. These peptides are believed to act synergically with other postprandial GI signals and cause satiation leading to meal termination.[48] GLP-1 exerts glucoregulatory actions via augmenting the insulin response to nutrients, slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies.[49] In addition to peripheral actions, both GLP-1 and its receptor are expressed in the central nervous system as shown by both human and animal studies.[50,51] GLP-1 expands islet mass by stimulating pancreatic β-cell proliferation and induction of islet neogenesis in rodents. GLP-1 also promotes cell differentiation, from exocrine cells or immature islet progenitors; toward a more differentiated β-cell phenotype.[52] In one study four groups (lean, non-operated obese, obese 9months after JIB and obese 20years after JIB) of six females were given a mixed meal (280kcal). Plasma samples were obtained every 10min for 60-min postprandially and were analysed for glucose, insulin and GLP-1. A reduction in BMI was seen for the two patient groups operated with JIB. Surgery by JIB resulted in a reduction of glucose and insulin values. In the obese subjects 20years after JIB both fasting and postprandial GLP-1-values were markedly elevated compared with the other three groups; whereas plasma glucose and insulin concentrations were maintained at normal levels.[53] Gut peptides acting both peripherally and centrally, contribute to glycaemic control and regulate food intake. Following RYGB even with minimal changes in mean BMI there is a significant decrease in blood glucose and insulin. Hence after both RYGB and JIB, changes in the incretin hormone response may contribute to the improved glycaemic control.[40]

OXM along with GLP-1 and GLP-2 belongs to the enteroglucagon family of peptides (due to shared immunoreactivity with glucagon) which were originally identified within the distal intestinal L-cells and are produced by differential splicing of the preproglucagon gene by proconvertase I.[52,54] In humans, intravenous OXM infusions acutely decrease hunger and single-meal food intake, without reducing the palatability of the meal.[55] In a 4-week human trial repeated OXM injections decreased body weight by 0·5kg/week more than placebo.[56] OXM also reduced single-meal intake at the beginning and end of the same study by 25% and 35%, respectively.[56] In another study, GI hormone responses to meals in morbidly obese patients before and after RYGB or VBG were evaluated. The 3-h integrated enteroglucagon response to glucose increased markedly after RYGB. This increase in enteroglucagon occurred at the same time as development of dumping symptoms, which occurred exclusively in RYGB patients after glucose intake. Hence, RYGB is associated with an exaggerated enteroglucagon response to glucose and these hormones appear to be a marker of the dumping syndrome in postoperative patients.[57] Enteroglucagon concentration has also been shown to be elevated in the peripheral blood following JIB and BPD.[58,59]

GIP is an incretin peptide like GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion. Both share common actions on islet β-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of β-cell proliferation and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. GLP-1 and GIP integrate nutrient-derived signals to control food intake and energy absorption.[49]

As GIP along with GLP-1 has been found to have a profound incretin effect in humans, a study was conducted to examine the long-term effect of JIB on glucose metabolism. JIB resulted in an elevation of postprandial GIP and GLP-1 plasma concentrations and a reduction of glucose and insulin concentrations.[53] The improved glucose metabolism can be explained by either the postoperative weight loss on itself or a combination effect of weight loss and increased concentrations of incretin hormones GIP and GLP-1. A group evaluated the early effect of RYGB on hormones involved in body weight regulation and glucose metabolism. Ten patients with a mean preoperative BMI of 46·2kg/m (40–53kg/m) underwent RYGB. Six patients had type 2 diabetes mellitus and were treated with oral hypoglycaemic agents. Preoperatively and 3weeks following surgery, fasting GIP and other gut hormones were measured. Interestingly RYGB significantly reduced GIP levels in diabetic patients, whereas no changes in GIP levels were found in nondiabetics.[60] In another study to elucidate the differential role of the jejunum and ileum in the regulation of secretion of the gut hormones, plasma GIP was measured during fasting and after a test meal in 34 obese patients of whom 29 had a JIB. The major finding was that JIB reduces the level of GIP.[61] This is consistent with reduced GIP after BPD.[59]

CCK is an established brain–gut peptide that plays an important regulatory role in GI function. It inhibits gastric motility and emptying via a capsaicin sensitive vagal pathway. The effects on emptying are via its action on the proximal stomach and pylorus. CCK is also involved in the regulation of food intake. It is released in the gut in response to a meal and acts via vagal afferents to induce satiety. Other neurotransmitters such as serotonin and noradrenalin may be implicated with CCK in the co-ordination of gastrointestinal activity.[62]

CCK responses to meals do not alter after RYGB or VBG. This suggests that CCK does not mediate an endocrine satiety effect of surgery.[57] CCK was determined after an overnight fast and after the administration of an acidified (pH3) liquid meal in eight subjects before and after VBG. Blood samples were taken 45min before the meal, 5min after and then every 30 min for 3h. There were no differences between groups in basal CCK levels. However, the peak of CCK after the meal was significantly higher in obese patients following VBG and when compared with the control group. These changes could contribute to the satiety effects of gastric restrictive operations.[63] One study looked at the CCK levels 20years after JIB. BMI changed from 44±4kg/m2 presurgery to 31±4kg/m2 in seven subjects 20years after surgery. Serial blood samples were obtained every 10min after intake of a 280-kcal meal. After JIB postprandial CCK was elevated compared to non-operated obese subjects. Similarly, basal levels of CCK were elevated in the operated group.[64] JIB surgery for obesity increases the risk of gallstone formation and the incidence is greater in patients with a long segment of ileum left in continuity. However, postoperative changes in plasma CCK levels neither explain the increased risk of gallstone formation after bypass surgery nor the higher incidence with a long ileum left in continuity in the bypass.[65] No change in CCK release has been observed after RYGB.[57,60]

PP belongs to a family of peptides including NPY and PYY. PP is released from the pancreas in response to ingestion of food. Plasma PP has been shown to be reduced in conditions associated with increased food intake and elevated in anorexia nervosa.[66] Intravenously administered PP induces negative energy balance by decreasing food intake and gastric emptying while increasing energy expenditure. The mechanism involved is modification of expression of feeding-regulatory peptides (decrease in orexigenic NPY, orexin and ghrelin along with an increase in anorexigenic urocortin) and activity of the vagovagal or vagosympathetic reflex arc. PP reduces leptin in white adipose tissue and ACTH-releasing factor gene expression.[15]

In one study, 29 obese patients who underwent JIB were compared with five preoperative obese subjects during fasting and after a test meal. There were no differences in PP concentrations between the groups.[61] Another study looked at the influence of morbid obesity and RYGB on PP in six morbidly obese patients before and 6–9months after surgery. PP levels were determined in the fasting state and after a standardized test meal. Fasting levels of PP were not different between the pre- and postoperative states. However, the postprandial response showed a significant reduction of PP postoperatively compared with the preoperative values.[67] These findings were consistent with a comparison made between RYGB and GB by another study group.[40] From the above results it seems that PP levels are not significantly altered by any of the bariatric operations.

The changes in gut hormones after GB and RYGB are summarised in Table 1 and Table 2 .

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