FEATURED NEW INVESTIGATOR Potential mechanisms by which bariatric surgery improves systemic metabolism ANOOPA A. KOSHY, ALEXANDRIA M. BOBE, and MATTHEW J. BRADY CHICAGO, ILL Over the past several decades, excessive body weight has become a major health concern. As the obesity epidemic continues to expand, metabolic disorders associated with excess body weight, including type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease, have exponentially increased. Dysregulation of satiety hormones and factors that regulate long-term energy storage can disrupt normal metabolic functions and lead to excess body fat. While diet and exercise seem to provide a logical means for weight loss, an unhealthy lifestyle coupled to responses initiated by perceived energy deficit impede sustained long term weight loss. Furthermore, because of the additional lack of effective pharmaceutical interventions to treat excess body weight, patients with severe obesity resort to bariatric surgery as an effective alternative for treatment of obesity and resolution of its associated comorbidities. Interestingly, the precise method by which bariatric surgery promotes rapid improvement in systemic metabolism and long-term weight loss remains incompletely understood and may vary between procedures. Multiple mechanisms likely contribute to the improved glucose metabolism seen after bariatric surgery, including caloric restriction, changes in the enteroinsular axis, alterations in the adipoinsular axis, release of nutrient-stimulated hormones from endocrine organs, stimulation from the nervous system, and psychosocial aspects including a dramatic improvement in quality of life. The current review will highlight the potential contribution of these responses to the improvement in systemic energy metabolism elicited by bariatric surgery. (Translational Research 2013;161:63–72) Abbreviations: BMI ¼ body mass index; BPD/DS ¼ biliopancreatic diversion/duodenal switch (BPD/DS); GIP ¼ glucose-dependent polypeptide; GLP-1 ¼ glucagon-like peptide 1 (GLP-1); HOMA ¼ homeostasis model assessment; LAGB ¼ laparoscopic adjustable gastric band; PYY3-36 ¼ peptide YY 3-36; RYBG ¼ Roux-en-Y gastric bypass; SG ¼ sleeve gastrectomy; VLCD ¼ very low calorie diet Anoopa A. Koshy, MD, is a Fellow in the Section of Endocrinology, Diabetes, and Metabolism at the University of Chicago. Her article is based on a presentation given at the Combined Annual Meeting of the Central Society for Clinical Research and Midwestern Section American Federation for Medical Research held in Chicago, Ill, on April 2012. From the Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Ill. Submitted for publication July 12, 2012; revision submitted September 25, 2012; accepted for publication September 27, 2012. Conflict of interest: None. Ó 2013 Mosby, Inc. All rights reserved. Reprint requests: Anoopa A. Koshy, Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, 900 East 57th Street, KCBD 8124, Chicago, IL 60637; e-mail: Anoopa.Koshy@uchospitals.edu. 1931-5244/$ - see front matter http://dx.doi.org/10.1016/j.trsl.2012.09.004 63 64 Koshy et al In obese patients with associated comorbidities, maintenance of weight loss is difficult to accomplish. While conventional methods of diet and exercise are used for weight control, the body exhibits robust responses to counter a state of energy deficit required for weight loss.1 Kennedy in 1953 first suggested the set point model, a regulated phenomenon of fat storage in which the brain senses signals produced by adipose tissue and compares it with a target level of body fat.1 The levels of signal compared with the set point trigger changes in energy intake and expenditure, bringing actual levels of body fat back in line with the target.1,2 This ‘‘lipostatic model’’ of body fat regulation is based on the concept of a negative feedback system that has gained popularity since the 1990s due to the discovery of leptin.1,2 As an individual becomes obese, the increased adiposity causes the set point to increase. The new higher set point is actively defended by the brain through the hunger drive and reduced metabolic rate and does not appear to be lowered in concert with weight loss.3 This set point model in which the body defends a higher level of adiposity is often used to explain the difficulty in maintaining weight after acute weight loss.3 Studies have shown that individuals maintaining a reduced body weight after non-surgical weight loss are inclined towards greater energy intake. Weight-reduced subjects report increased food craving, a decreased perception of actual food intake, and an increased preference for calorically dense foods.4-6 This imbalance where weight-reduced subjects consume more calories than are needed to maintain their weight persists.7 Cornier et al8 compared pre- and post- meal ratings of hunger and satiation in never-obese and reduced-obese adults who were studied on a weight maintenance diet and again during 3 days of 50% overfeeding. The neverobese subjects demonstrated an approximate 35% decrease in pre-meal hunger ratings and 35% increase in post-meal satiety ratings during overfeeding compared with the weight maintenance diet.8 Reduced-obese subjects reported no changes in pre-meal hunger ratings and an 11% increase in post-meal satiety ratings during overfeeding. After overfeeding, never-obese women, but not reduced-obese men or women, significantly reduced their unrestricted caloric intake below weight maintenance needs.8 These data suggested that reduced-obese subjects did not experience a change in hunger during overfeeding and only experience a small increase in satiety compared with significant changes in both of these parameters in never-obese subjects.7 In addition, reduced-obese subjects did not make any compensatory adjustments to resist sustained weight gain.7 Individuals with severe obesity cannot simply rely on conventional methods as a means for sustainable weight Translational Research February 2013 loss. Hence, surgical treatment has become increasingly popular as an effective alternative to significant weight loss and comorbidity resolution. As the prevalence of obesity has sky-rocketed in the past decade, the volume of bariatric surgeries performed has also been on the rise—by 900% in the United States and 350% in other parts of the world.9 Eligibility criteria for bariatric surgery defined by the NIH include a body mass index (BMI) of 40 or more, or a BMI between 35 and 39.9 and a serious obesity-related comorbidity such as type 2 diabetes, hyperlipidemia, hypertension, or obstructive sleep apnea. Prior attempts at weight loss with diet and exercise must have also been tried without success. Not all surgical procedures have the same degree of success in maintaining weight loss as bariatric surgery. For example, liposuction has been shown to be ineffective in sustaining weight loss as evidenced by a randomized-controlled trial to determine the 1 year impact of liposuction in non-obese women.10 They discovered that fat removed during liposuction eventually returned within 1 year and was redistributed to other areas of the body, especially the upper abdomen, shoulders, and triceps.10 Bariatric surgery gained popularity since it is the only treatment shown to produce significant and sustainable weight loss. The development of laparoscopic techniques, increased physician awareness, and increased patient knowledge also contributed to the rise in bariatric surgeries performed nationally.9 Also, bariatric surgery has been shown to improve and in many cases, resolve obesity-related comorbidities and significantly improve quality of life.9 BARIATRIC SURGERY PROCEDURES Bariatric surgery decreases energy intake 2 ways—by restriction and malabsorption.9 The first method is referred to as restriction because it limits the amount of calories consumed on a daily basis. Procedures such as the laparoscopic adjustable gastric band (LAGB) and the vertical (sleeve) gastrectomy (SG) are primary examples of this type of surgery. In addition to food restriction, caloric malabsorption can be induced by limiting energy uptake by either bypassing segments of the small intestine or rearranging the small intestine to separate the flow of food from the flow of bile and pancreatic juices.9 Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion with or without duodenal switch (BPD and BPD/DS) are examples of procedures that have a malabsorptive component.9 All current bariatric surgeries incorporate 1 or both of these components to result in weight loss. There are 4 major types of bariatric surgeries that are currently performed in the United States today. Translational Research Volume 161, Number 2 LAPAROSCOPIC ADJUSTABLE GASTRIC BAND The laparoscopic adjustable gastric band (LAGB) is a synthetic band that is placed just below the gastroesophageal junction, creating a gastric pouch. The gastric band can be inflated or deflated to alter the degree of constriction around the stomach, and subsequently the patient is able to limit caloric intake and maintain satiety by delaying gastric emptying. Weight loss after LAGB has been reported as variable and a recent meta-analysis reported a 48% excess body weight loss (EBWL).11 LAGB had lower perioperative complications compared with other bariatric surgery procedures. It also had a 70% resolution of type 2 diabetes in patients with mild obesity (BMI 30–40 kg/m2). However, in patients with a higher BMI, the resolution rate was only 48%. The most common complaint against LAGB was inadequate weight loss because up to 20% of patients failed to lose sufficient body weight (.10% of their initial body weight), a third of the patients had their bands removed after 9 years, and 24% required another operation. However, it had the safest 30-day post-mortality, 0%–0.1%, making LAGB the safest bariatric surgery option in mildly obese patients.9 SLEEVE GASTRECTOMY The sleeve gastrectomy (SG) is a procedure in which much of the greater curvature of the stomach is removed. It was initially performed as a first part of a 2-part procedure that included a biliopancreatic diversion/duodenal switch, but later began to be performed on its own when it was realized adequate weight loss occurred in these patients before the second part of the procedure was performed. The observed %EBWL was close to 50% at 6 months and 60% at both 1 and 2 years, with no difference in outcomes of the morbidly obese (BMI .40 kg/m2 ) and the super-obese (BMI .50 kg/m2).9 Weight loss tended to be greater than RYGB but inferior to BPD/DS. Nutritional deficiencies were rare, except for the potential risk of B12 deficiency caused by decreased production of intrinsic factor. Compared with other bariatric surgeries, the outcomes for SG were similar, despite lacking a malabsorptive component. Data for resolution of comorbidities has been limited, but initial data showed 66% for diabetes, 88% for hypertension, and 87% for sleep apnea in super-obese patients.12 ROUX-EN-Y GASTRIC BYPASS SURGERY Roux-en-Y gastric bypass surgery (RYGB) accounts for 60% of bariatric surgeries and is the most common type of bariatric surgery performed in the United States.9 It was first developed in the 1970s as a loop gastrojejunostomy and because of the high incidence of bile reflux, it was modified to the Roux-en-Y configura- Koshy et al 65 tion. The restrictive component of the procedure consists of the creation of a gastric pouch by using the upper part of the stomach near the gastroesophageal junction. The malabsorptive component of the procedure involves dividing the jejunum into an upper biliopancreatic limb and a lower limb. Next, the Roux limb is brought up to the level of the gastric pouch, and anastamosed to the gastric pouch bypassing potential release of food-stimulated gut hormones and absorption of nutrients in the duodenum and proximal jejunum. The biliopancreatic limb and the Roux limb are then connected by a distal jejunojejunostomy, decreasing the amount of time bile and pancreatic enzymes can mix with food.9 Although RYGB is a longer and more difficult procedure, it had a significant impact on the resolution of comorbidities—77% to 90% for type 2 diabetes, 68% to 100% for hyperlipidemia, 58% to 77% for hypertension, 68% to 92% for obstructive sleep apnea.11 Dumping syndrome was more commonly reported with RYGB, which although bothersome to the patient can be helpful in making healthier food choices. RYGB had fewer anatomic long term complications compared to laparoscopic gastric banding. Thirty-day postoperative mortality was 0.5% and mortality improved further in high volume centers.11 BILIOPANCREATIC DIVERSION/DUODENAL SWITCH The biliopancreatic diversion/duodenal switch (BPD/ DS) was developed by Hess and Hess by combining the DeMeester et al duodenal switch and the Scopinaro biliopancreatic diversion.13–15 The BPD/DS procedure combines restrictive and malabsorptive elements to achieve and maintain the best reported long-term percentage of excess weight loss among modern weight-loss surgery procedures. Buchwald et al11 reported an estimated %EBWL of 70%. The restrictive component includes a partial gastrectomy, along the greater curvature of the stomach. Unlike the unmodified BPD and RYGB, which both employ a gastric ‘‘pouch’’ and bypass the pyloric valve, the DS procedure keeps the pyloric valve intact, eliminating dumping syndrome. The malabsorptive component of the BPD/DS procedure rearranges the small intestine to separate the flow of food from the flow of bile and pancreatic juices. These divided intestinal paths are rejoined further down the digestive tract into a common tract where the food and digestive juices mix and limited fat absorption. Despite its effectiveness in weight loss, BPD/DS accounts for only 3% of bariatric surgeries nationally. Historically, it has one of the highest mortality rates (1%) compared with the other bariatric surgeries and poses a high risk of nutritional deficiencies requiring close monitoring and rigorous replacement of nutritional needs after surgery. However, recent studies 66 Translational Research February 2013 Koshy et al have shown that BPD/DS provides a greater percentage of resolution of obesity associated comorbidities.11 Average comorbidity resolution rates are 99% for type 2 diabetes, 99% for hyperlipidemia, 83% for hypertension, and 92% for obstructive sleep apnea.11 In a recent study, BPD/DS was shown to be significantly more efficacious than Roux-en-Y gastric bypass surgery at resolving diabetes.16 BENEFICIAL EFFECTS OF BARIATRIC SURGERY Two recently published studies revealed bariatric surgery resulted in better glucose control than did medical therapy in severely obese patients with type 2 diabetes.17,18 Mingrone et al17 used a non-blinded, singlecenter, randomized trial with 60 patients with a BMI of 35 or more and a history of at least 5 years of diabetes and randomly assigned them to receive conventional medical therapy or undergo either Roux-en-Y gastric bypass surgery or biliopancreatic diversion. Their results showed that diabetes remission did not occur in any patients in the medical-therapy group, but occurred in 75% in the Roux-en-Y gastric-bypass group and 95% in the biliopancreatic-diversion group. At 2 years, the average baseline hemoglobin A1c (8.65 6 1.45%) had decreased in all groups, but patients in the 2 bariatric surgery groups had the greatest degree of improvement (average glycated hemoglobin levels, 7.69 6 0.57% in the medical-therapy group, 6.35 6 1.42% in the gastric-bypass group, and 4.95 6 0.49% in the biliopancreatic-diversion group).14 In a separate study, Schauer et al18 evaluated the efficacy of intensive medical therapy versus medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy in 150 obese patients with uncontrolled type 2 diabetes. The authors concluded that 12 months of medical therapy plus bariatric surgery achieved better glycemic control in obese patients than medical therapy alone. These studies demonstrated surgical treatment of obesity is superior to improving glycemic control in type 2 diabetics than medical treatment alone. The length of diabetes diagnosis also plays a role in the maintenance of remission of type 2 diabetes after bariatric surgery. Ramos et al19 suggested that resolution of type 2 diabetes is most effective after bariatric surgery when the diagnosis of diabetes has been made less than 5 years at the time of surgery. They studied the medical records of 72 obese patients with type 2 diabetes who underwent Roux-en-Y gastric bypass surgery between 2000 and 2007. Their findings showed that 66 patients (92 %) had a reversal of their diabetes.19 Within 3 to 5 years after surgery, 14 (21 %) of the 66 patients experienced a recurrence of their type 2 diabetes, as evidenced by blood work or re-initiation of diabetes medications. The patients who did not have recurrence of diabetes lost more weight initially and maintained a lower mean weight throughout the 5 years of followup, although both groups regained similar amounts of weight.19 Although there was no significant association between higher recurrence rate and BMI before surgery, the authors discovered longer duration of type 2 diabetes before surgery correlated with a higher probability of diabetes recurrence.19 Patients with more than a 5-year duration of type 2 diabetes prior to bariatric surgery were 3.8 times more likely to have recurrence of type 2 diabetes compared with patients with less than a 5-year history of diabetes.19 These findings suggest residual islet cell function must be present in order for bariatric surgery to be the most effective in resolving type 2 diabetes, and that early surgical intervention in the obese, diabetic population would be the most effective in improving the durability of remission of type 2 diabetes when the diagnosis has been made less than 5 years at the time of surgery. MECHANISMS BY WHICH BARIATRIC SURGERY IMPROVES GLUCOSE METABOLISM Several mechanisms have been proposed to explain improved glucose metabolism after bariatric surgery (see Fig. 1), and likely multiple changes are responsible for the beneficial effects. Physical changes during surgery, including the restrictive and malabsorptive properties of bariatric surgery influence body mass. The interactions between molecular signals, including signals to and from the brain, adipose tissue, pancreas, and gastrointestinal tract, are important in regulating the anabolic and catabolic responses that drive metabolic rate. Both changes in the adipoinsular and enteroinsular axis contribute toward resolution of diabetes after bariatric surgery. Subsequent changes in hormone levels have shown to improve insulin sensitivity in patients, further indicating the importance of understanding the complexity of these signals between systems. CALORIC RESTRICTION It is well-known that changes in diet can significantly improve glucose tolerance in diabetics. In the standard postoperative period following gastric bypass surgery, patients have minimal caloric intake during the first week. While short-term starvation of 4 to 7 days induces insulin resistance,20,21 lesser degrees of energy restriction have been shown to improve insulin sensitivity.22,23 Ash et al24 studied the impact of a calorie restricted diet (1400–1700 kcal/day) on 51 men with type 2 diabetes in a randomized controlled trial. Average weight loss at 4 weeks was 6.4 6 4.6 kg, while average decrease in body fat was 1.5 6 1.9%, and average decrease in HbA1c was 1.0 6 1.4%. Another study by Translational Research Volume 161, Number 2 Koshy et al 67 Fig. 1. Impact of bariatric surgery on systemic metabolism. A complex interrelated network of factors mediates weight loss and improvement in global insulin sensitivity following bariatric surgery. Decreased caloric intake and absorption, changes in hormonal secretion and/or sensitivity (adipoinsular and enteroinsular axes), and a resetting of the central nervous set point for the body all likely contribute to weight loss and improved quality of life. Heilbronn et al25 showed that significant changes in glucose metabolism were noted as early as 4 weeks after initiation of the calorie-restricted diet. Average weight loss for 45 overweight men with a BMI of 33 was 3.6 6 0.4 kg after a calorie-restricted diet. Fasting glucose significantly decreased by 6% and HbA1c decreased by 3%. A recent study showed that both beta cell failure and insulin resistance can be reversed by dietary restriction of energy intake.26 These studies indicated that severe caloric restriction alone can lead to rapid improvement in glucose metabolism in obese individuals with type 2 diabetes in a short period of time, but it is not sufficient to fully explain the effects of bariatric surgery on weight loss, indicating that other mechanisms must also be involved.20 Another study compared obese patients who underwent caloric restriction and/or gastric bypass surgery.27 They studied 8 severely obese patients who underwent a 6-day very low calorie diet (VLCD), approximately 456 kcal/day, followed 1–3 weeks later by RYGB. Insulin resistance was measured by short intravenous insulin tolerance test and by homeostasis model assessment (HOMA) before and again 6 days after the VLCD and after RYGB.27 In another group of 24 matched patients, HOMA assessments were made before and 6 days after RYGB. HOMA-IR fell significantly from 6.8 6 4.9 to 4.3 6 2.9, P , 0.05, after 6 days of VLCD, but this was less than the fall following RYGB (6.8 6 4.9 to 1.5 6 0.4, P , 0.01). Control patients who underwent RYGB alone, reduced their HOMA-IR to 1.5 6 0.9 following the operation which was not significantly different from the VLCD then RYGB group.27 Their findings demonstrated that calorie restriction was shown to reduce HOMA-IR significantly, which was then further and significantly reduced by subsequent RYGB. The change in HOMA after VLCD followed by RYGB was not different from the change after RYGB alone.27 This suggests that RYGB has a beneficial effect on insu- lin resistance over and above than seen with caloric restriction alone. ENTEROINSULAR AXIS: THE FOREGUT AND HINDGUT HYPOTHESES The concept of an enteroinsular axis as a mechanism for intestinal regulation of insulin secretion has been suggested as a potential mechanism for the rapid improvement in glucose metabolism following bariatric surgery.28,29 The enteroinsular axis is a regulatory system in which insulin secretion from pancreatic beta cells is partially influenced by hormones from the gastrointestinal tract. A post-surgery alteration in the ‘‘incretin effect’’ has been implicated as a potential mechanism for the rapid improvement in insulin secretion.30 The ‘‘incretin effect’’ is defined as the stimulation of insulin secretion mediated by glucagon-like peptide 1 (GLP-1) and glucose-dependent polypeptide (GIP) secreted from the gut.30 Early studies showed that GLP-1 and GIP levels were markedly increased by oral glucose after bariatric surgery.31 Other studies showed no change in GIP levels of nondiabetic subjects or diabetic subjects after bariatric surgery, indicating that the enteroinsular axis is likely not the only mechanism involved in mediating effects of bariatric surgery in systemic metabolism.32 The fact that GIP levels are not always affected indicates that more studies are needed to clearly define the impact on gut peptides and their role in mediating effects of bariatric surgery. The foregut and the hindgut hypotheses have been proposed to explain the early effects of metabolic surgery.33 The foregut hypothesis states that the exclusion of the proximal small intestine reduces or suppresses the secretion of putative anti-incretin hormones, with a consequent improvement in blood glucose control.33 The hindgut hypothesis states that diabetes control results from the rapid delivery of nutrients to the distal intestine, thereby enhancing the release of hormones such 68 Translational Research February 2013 Koshy et al as GLP-1.33 Consistent with the lower intestinal hypothesis, RYGB and DS, the 2 bariatric surgeries most noted for rapid type 2 diabetes remission, create GI shortcuts for food to access the distal bowel. After DS, which conducts food directly from the stomach to the ileum, postprandial GLP-1 levels are increased. Because RYGB diverts nutrients away from the duodenum, the surgery might theoretically lower postprandial GLP-1 levels. However, recent studies show that meal-stimulated secretion of GLP-1 and other L-cell peptides such as PYY is substantially increased after RYGB.31,34-36 Consistent with the elevated postprandial GLP-1 secretion, post-RYGB patients demonstrate an increased incretin effect.37 The levels of GLP-1 and other gut peptides not all detailed in this review are increased by diverting procedures, such as DS and RYGB.38,39 An excellent summary of gut hormone changes after Roux-en-Y gastric surgery can be found in Table 1 in a recent publication by Michalakis and le Roux and also in Table 1 by another review paper by Pournaras and le Roux.38,39 Future studies investigating the exact mechanisms resulting in changes in gut peptide levels may provide greater insight into their role in mediating beneficial effects of bariatric surgery. PEPTIDE YY 3-36 Recent studies suggest that the gut hormone peptide YY 3-36 (PYY3-36), an anorectic hormone produced by the enteroendocrine L-cells in the gut may partially mediate effects of gastric bypass surgery on appetite and weight loss.34,40,41 It was recently discovered that PYY3-36 reduced feeding in obese rodents and humans and was found to modulate neuronal activity in the brain.42 Studies in rodents identified the hypothalamus, vagus, and brainstem regions as potential sites of action.42 More recently, studies utilizing functional brain imaging techniques in humans showed that PYY3–36 was found to modulate neuronal activity within hypothalamic and brainstem, and brain regions involved in reward processing.43 These findings suggested that low circulating PYY concentrations lead toward the development of obesity. Patients with reduced postprandial PYY release exhibited lower satiety and circulating PYY levels that correlated negatively with markers of adiposity.43 In addition, mice lacking PYY were noted to be hyperphagic and became obese. In contrast, chronic PYY3–36 administration to obese rodents reduced adiposity, and transgenic mice with increased circulating PYY were resistant to diet-induced obesity.42 Recent studies in humans suggested PYY3–36 may partly mediate the reduced appetite and weight loss benefits observed post-gastric bypass surgery. In 1997 Naslund et al40 measured fasted and meal-stimulated PYY levels in control subjects and patients who had undergone jejunoileal bypass 20 years previously. Findings showed that both fasting and meal-stimulated PYY levels were markedly elevated. In 2003, increased circulating PYY were proposed to play a role in regulating the weight changes seen following bariatric surgery.41 They undertook studies in rats in which the total length of the gut remained unaltered but where a 10 cm ileal segment was transposed to the proximal jejunum. Rats who had undergone ileal transposition ate less, had reduced body weight, increased PYYexpression within the transposed segment and increased circulating PYY levels.41 Soon after, Korner et al31 discovered that patients who had undergone RYGB had significantly higher mealstimulated PYY levels compared with weight-matched controls or lean control subject. This finding of increased nutrient-stimulated PYY levels following RYGB has been confirmed by several independent investigators34–36 and may contribute the improvement in weight loss that is seen after RYGB and DS. GHRELIN Ghrelin is a 28 amino acid hunger-stimulating hormone produced by the stomach that has been implicated in several physiological functions, including growth hormone release, gastric emptying, and body weight regulation.44 The secretion of the upper GI hormone ghrelin has also been hypothesized to contribute to the anorexic and antidiabetic affects of RYGB.44,45 A study found that human 24-h ghrelin profiles displayed marked preprandial surges followed by postprandial suppression, and circulating levels increased in proportion to lost weight with dieting.37 This implicated ghrelin in mealtime hunger and in the adaptive increase of appetite that resists nonsurgical weight loss. Since 90% of ghrelin is produced by the stomach and duodenum, both of which are altered by RYGB, it was hypothesized that ghrelin levels change after bariatric surgery. Researchers found that ghrelin levels in post-RYGB patients were extremely low throughout the 24-h period.37 Since then, other prospective studies have shown that ghrelin levels fall after RYGB. Ghrelin can also stimulate insulin counter-regulatory hormones, suppress adiponectin, block hepatic insulin signaling, and inhibit insulin secretion.37 Since all of these actions acutely increase blood glucose levels, the glycemic improvement seen after bariatric surgery may arise from reduced ghrelin secretion. ADIPOINSULAR AXIS Another potential contributor to the rapid effect of bariatric surgery on glucose metabolism is the adipoinsular axis. Fat is the largest reservoir of energy storage Translational Research Volume 161, Number 2 in the body and secretes a growing number of endocrine factors that influence feeding behavior and insulin sensitivity in other tissues. Dysregulation of the adipoinsular axis during obesity is a major contributor to the development of insulin resistance and type 2 diabetes. Recent literature has shown that obesity is associated with a low-grade inflammatory state and proinflammatory cytokines may play an important role in mediating detrimental effects of obesity on metabolism.46-48 However, the acute impact of bariatric surgery directly on adipocytic insulin sensitivity vs the secondary effects arising from long term weight remain controversial and under study. Elevation of proinflammatory cytokines, such has TNF-a and IL-6, could cause insulin resistance by interfering with insulin signaling and downregulating peroxisomal proliferatoractivated receptor-g receptors.49,50 Studies have shown that increased serum levels of inflammatory biomarkers such as CRP exist in obese subjects and levels of CRP decrease significantly after bariatric surgery.46-48 Vasquez et al48 examined 26 morbidly obese patients before and 4 months after bariatric surgery and found that circulating levels of E-selectin, P-selectin, plasminogen activator inhibitor-1, and von Willebrand factor decreased significantly after bariatric surgery. Positive correlations were found between changes in adiposity and insulin sensitivity index and between changes in c-reactive protein, sialic acid, and changes in endothelial function.48 This suggests that insulin sensitivity and adiposity appear to play roles in obesity-related low grade inflammation that contribute to endothelial dysfunction observed in morbid obesity and may potentially be reversible after bariatric surgery. Interestingly, thiazolidinediones (TZDs), medications that are commonly used to treat type 2 diabetes, have been shown to increase systemic insulin sensitivity by increasing new fat cell differentiation. This suggests that increased fat mass per se does not lead to systemic insulin resistance. When adipocytes no longer safely store free fatty acids, they escape into the circulation resulting in ectopic accumulation in skeletal muscle and liver and contribute to the development of insulin resistance. This raises the question: if adipose tissue was allowed to expand beyond the limits under normal physiological conditions, would it be possible to prevent ectopic lipid accumulation and the eventual dysregulation of adipocyte function? This concept was tested using ob/ob mice, which were deficient in leptin.51 Their study showed that obese and leptin deficient ob/ob mice through transgenic manipulation were induced to gain 30 g more fat mass, but their metabolic dysfunction was completely resolved after the weight gain because their increased fat mass removed excess free fatty acids from the bloodstream and other tissues for storage in the Koshy et al 69 fully functional adipocytes.51 This implies that improved adipocyte function independent of weight loss can exert profound effects on systemic insulin sensitivity. Taken together, this suggests that rapid improvement insulin sensitivity following bariatric surgery is a result of a change in insulin action at the cellular level of the adipocytes. ROLE OF THE CENTRAL NERVOUS SYSTEM The regulation of hunger drive and food intake relies on a complex neuroendocrine network integrating central nervous pathways with external signals.52 The neural pathways regulating food intake and energy include the homeostatic and hedonic systems. The arcuate nucleus plays a major role in the homeostatic system; neurons in the arcuate nucleus have receptors for gastrointestinal hormones and adipokines such as leptin, grhelin, PYY, and GLP-1.52 The reward system is constituted by the mesolimbic pathway, which extends from the ventral tegmental area to the nucleus accumbens and includes the amygdala and the hippocampus.52 Also, the density of dopamine type 2 (D2) receptors in mesolimbic brain areas have been found to be markedly decreased in severely obese patients, similar to that seen in drug addiction.53,54 These findings suggest that there could be possible structural changes that occur in the brain that parallel changes in metabolism observed after bariatric surgery. In fact, another study provided evidence that D2 receptor density in the reward-processing brain areas rapidly increases after gastric bypass surgery.55 This could be supported by changes in food preferences seen in patients after bariatric surgery, which might be attributable to an effect on the reward system of the brain.52 Bariatric surgery has been shown to decrease appetite, promote satiety, and increase energy expenditure through actions mediated by the CNS.52 Since weight loss by conventional means leads to increased appetite and calorie conservation, the reduced appetite seen in patients after bariatric surgery has been attributed to changes in gut hormones (like peptide YY, ghrelin, and GLP-1 previously mentioned).52 The CNS plays an important role in regulating systemic metabolism through multiple mechanisms, including effects on insulin secretion, hepatic glucose production, and metabolic rate. A recent study showed that hedonic hunger is increased in severely obese patients and reduced after gastric bypass surgery.56 Severely obese patients who had not undergone gastric bypass surgery (n 5 123), gastric bypass patients (n 5 136), and nonobese control subjects (n 5 110) were examined utilizing the Power of Food Scale (PFS)-a questionnaire that 70 Koshy et al measures an individual’s motivation to consume highly palatable foods. Compared with nonobese control subjects, severely obese patients displayed a marked increase in hedonic hunger as reflected by higher PFS scores that was not observed in gastric bypass surgery patients, suggesting that hunger drive is reduced in patients after gastric bypass surgery. Future studies aimed at investigating the gut-brain axis mechanisms that mediate improved metabolism seen after bariatric surgery may lead to new perspectives leading to more effective medical therapies for severe obesity. PSYCHOSOCIAL ASPECTS AND QUALITY OF LIFE In additional to hormonal and nutritional changes, psychosocial variables also play an important but underappreciated role in the development of obesity as well as in the positive and negative weight loss results following bariatric surgery. Obesity has numerous psychological effects that affect quality of life and can have a profoundly negative impact on a patient’s perception of his or her health.57 This negative perception of themselves may be reflected in binge eating of perceived comfort foods and/or decreased social interaction and activity. Choban et al57 reported that severe obesity caused significantly decreased health status in 7 of 8 domains measured by the 36-item Health survey (SF36). The SF-36 is a questionnaire that measures 8 health concepts: physical functioning (limitations in performance of various physical activities), role-physical (limitations in daily activities as a result of physical health), role-emotional (limitations in daily activities as a result of emotional problems), bodily pain (measures pain-related functional limitations), vitality (measures energy level), mental health (measures the presence and degree of depression and anxiety), social functioning (measures limitations in social functioning) and general health (measures an individual’s perception of his or her overall health).58 The SF-36 scores are standardized, with the worst score being 0 to correlate with poor health, and the best score being 100 to correlate with good health. The quality of life in 155 patients with a BMI of 40–60 kg/m2 who were randomly assigned to undergo laparoscopic or open gastric bypass surgery was compared.58 Their study showed that SF36 scores that correlated with poor quality of life at baseline and found that the patients’ quality of life improved rapidly after surgery in both groups, but significantly more so in the laparoscopic gastric bypass surgery group.58 In the Swedish Obese Subjects study, patients reported peak improvements in health-related quality of life at 6 and 12 months postoperatively, but these improvements deteriorated slightly at 2 years Translational Research February 2013 postoperatively.59 At 2 years, however, improvements in quality of life were positively correlated with the amount of weight lost.59 This perception of improvement in quality of life alone may have a huge role in a patient’s ability to function in daily life and could affect metabolism after bariatric surgery Behavioral factors such as binge eating may also play a major role in weight regain after bariatric surgery and may be helpful in determining a positive outcome after surgery.60 On average, most patients lose 60% of excess weight after gastric bypass and 40% after vertical banded gastroplasty. In about 30% of patients, weight regain occurs at 18 months to 2 years after surgery.60 Binge eating behavior, which is common among the morbidly obese, may recur after surgery and is associated with weight regain. Green et al61 examined surgical outcome between 2 groups of patients undergoing Roux-en-Y gastric bypass surgery: those with presurgical binge eating and those without presurgical binge eating. Their study showed that compared with the non-binge eating group, the binge-eating group had significantly higher levels of disinhibited eating, hunger, and significantly lower levels of social functioning at presurgery and 6 months postsurgery.61 The binge eating group also had a significantly lower percentage of excess weight lost than the non binge-eating group at 6 months postsurgery.61 Their findings indicated a less successful outcome for the binge-eating patients compared with the non binge-eating patients.61 This suggests that behavioral aspects such as binge-eating may predispose a patient to poorer prognostic outcome compared with non-binge eaters and may play a bigger role in an effective outcome after surgery than previously realized. Psychosocial outcome after bariatric surgery is generally encouraging over the short term, but there are reports of poor adjustment after weight loss, including alcohol abuse, and suicide.60 Waters et al followed 157 patients for up to 2 years to determine the effects of gastric bypass on various mental health indices.62,63 Although there were significant improvements in scores for anxiety, depression, general health, positive well-being, self control, and vitality after 6 and 12 months, measures of mental health returned to preoperative levels after the second year after the postoperative weight stabilized.62,63 They concluded that patients may come to depend on the medical and psychological supports from their clinic visits and that when the frequency of these visits decreased after the first 2 years, their mental health improvement also declined.62 Long-term outcome data on psychosocial functioning are lacking and longitudinal studies are necessary to examine prognostic indicators and how they affect the long-term outcome of bariatric surgery. Translational Research Volume 161, Number 2 CONCLUSION Multiple mechanisms may contribute to the improved glucose metabolism including caloric restriction, changes in the enteroinsular axis, alterations in the adipoinsular axis, release of nutrient-stimulated hormones from endocrine organs, and stimulation from the nervous system, suggesting that the antidiabetic affect is not a result of one single mechanism alone. 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