Gut adaptation after gastric bypass in humans reveals metabolically significant shift in fuel metabolism.

OBJECTIVE: Roux-en-Y gastric bypass surgery (RYGB) is among the most effective therapies for obesity and type 2 diabetes, and intestinal adaptation is a proposed mechanism for these effects. It was hypothesized that intestinal adaptation precedes and relates to metabolic improvement in humans after RYGB. METHODS: This was a prospective, longitudinal, first-in-human study of gene expression (GE) in the "Roux limb" (RL) collected surgically/endoscopically from 19 patients with and without diabetes. GE was determined by microarray across six postoperative months, including at an early postoperative (1 month ± 15 days) time point. RESULTS: RL GE demonstrated tissue remodeling and metabolic reprogramming, including increased glucose and amino acid use. RL GE signatures were established early, before maximal clinical response, and persisted. Distinct GE fingerprints predicted concurrent and future improvements in HbA1c and in weight. Human RL exhibited GE changes characterized by anabolic growth and shift in metabolic substrate use. Paradoxically, anabolic growth in RL appeared to contribute to the catabolic state elicited by RYGB. CONCLUSIONS: These data support a role for a direct effect of intestinal energy metabolism to contribute to the beneficial clinical effects of RYGB, suggesting that related pathways might be potential targets of therapeutic interest for patients with obesity with or without type 2 diabetes.

Endoscopic ultrasound-guided sampling and profiling of portal circulation in human patients for metabolic research studies and biomarker assessment.

Portal and hepatic circulation can now be safely accessed using endoscopic ultrasound (EUS). EUS-guided needle access of the portal vein is performed clinically at select tertiary centers for measurement of portal pressure gradients in patients with chronic liver disease and sampling of portal venous thrombus to diagnose malignancy. We propose that this novel clinical technique can be applied in research studies to allow blood collection from and profiling of portal and hepatic circulation. In this technical report, we present and highlight the technical aspects, feasibility, and safety of EUS: guided portal venous blood collection. As a proof of the concept and the utility of this technique in metabolic research and biomarker assessment and discovery, we present a pilot metabolite profiling study of portal venous blood in a small cohort of patients with cirrhosis and a comparison with a group without cirrhosis. Despite the very small diameter of the endoscopic needle used for the blood collection, the portal samples have the same quality as those collected from systemic circulation, and they can be used for the same downstream applications. Finally, we propose an analytical workflow to screen for promising metabolites that could qualify for further studies to determine their utility as sensitive, early candidate biomarkers of hepatic fibrosis, portal shunt, and hypertension. We hope that this report could stimulate and facilitate the widespread use of EUS-guided techniques for the profiling of portal circulation, which could potentially open a new field of scientific inquiry.NEW & NOTEWORTHY The technical aspects, feasibility, and safety of endoscopic ultrasound (EUS)-guided needle access for portal venous blood collection are presented in this technical report. Despite the very small diameter of the endoscopic needle, portal blood samples have the same quality as those collected from systemic circulation. As a proof of the concept and the utility of this technique in metabolic research and biomarker assessment and discovery, we present a pilot metabolite profiling study of portal venous blood in a small cohort of patients with cirrhosis and a comparison with a group without cirrhosis.

Nonalcoholic fatty liver disease and portal hypertension.

Nonalcoholic fatty liver disease (NAFLD) is a substantial and growing problem worldwide and has become the second most common indication for liver transplantation as it may progress to cirrhosis and develop complications from portal hypertension primarily caused by advanced fibrosis and erratic tissue remodeling. However, elevated portal venous pressure has also been detected in experimental models of fatty liver and in human NAFLD when fibrosis is far less advanced and cirrhosis is absent. Early increases in intrahepatic vascular resistance may contribute to the progression of liver disease. Specific pathophenotypes linked to the development of portal hypertension in NAFLD include hepatocellular lipid accumulation and ballooning injury, capillarization of liver sinusoidal endothelial cells, enhanced contractility of hepatic stellate cells, activation of Kupffer cells and pro-inflammatory pathways, adhesion and entrapment of recruited leukocytes, microthrombosis, angiogenesis and perisinusoidal fibrosis. These pathological events are amplified in NAFLD by concomitant visceral obesity, insulin resistance, type 2 diabetes and dysbiosis, promoting aberrant interactions with adipose tissue, skeletal muscle and gut microbiota. Measurement of the hepatic venous pressure gradient by retrograde insertion of a balloon-tipped central vein catheter is the current reference method for predicting outcomes of cirrhosis associated with clinically significant portal hypertension and guiding interventions. This invasive technique is rarely considered in the absence of cirrhosis where currently available clinical, imaging and laboratory correlates of portal hypertension may not reflect early changes in liver hemodynamics. Availability of less invasive but sufficiently sensitive methods for the assessment of portal venous pressure in NAFLD remains therefore an unmet need. Recent efforts to develop new biomarkers and endoscopy-based approaches such as endoscopic ultrasound-guided measurement of portal pressure gradient may help achieve this goal. In addition, cellular and molecular targets are being identified to guide emerging therapies in the prevention and management of portal hypertension.

Portal Venous Metabolite Profiling After RYGB in Male Rats Highlights Changes in Gut-Liver Axis.

After Roux-en-Y gastric bypass (RYGB) surgery, the intestine undergoes structural and metabolic reprogramming and appears to enhance use of energetic fuels including glucose and amino acids (AAs), changes that may be related to the surgery's remarkable metabolic effects. Consistently, RYGB alters serum levels of AAs and other metabolites, perhaps reflecting mechanisms for metabolic improvement. To home in on the intestinal contribution, we performed metabolomic profiling in portal venous (PV) blood from lean, Long Evans rats after RYGB vs sham surgery. We found that one-carbon metabolism (OCM), nitrogen metabolism, and arginine and proline metabolism were significantly enriched in PV blood. Nitrogen, OCM, and sphingolipid metabolism as well as ubiquinone biosynthesis were also overrepresented among metabolites uniquely affected in PV vs peripheral blood in RYGB-operated but not sham-operated animals. Peripheral blood demonstrated changes in AA metabolism, OCM, sphingolipid metabolism, and glycerophospholipid metabolism. Despite enrichment for many of the same pathways, the overall metabolite fingerprint of the 2 compartments did not correlate, highlighting a unique role for PV metabolomic profiling as a window into gut metabolism. AA metabolism and OCM were enriched in peripheral blood both from humans and lean rats after RYGB, demonstrating that these conserved pathways might represent mechanisms for clinical improvement elicited by the surgery in patients. Together, our data provide novel insight into RYGB's effects on the gut-liver axis and highlight a role for OCM as a key metabolic pathway affected by RYGB.

Gastrointestinal Hormone Profiles Associated With Enteral Nutrition Tolerance and Gastric Emptying in Pediatric Critical Illness: A Pilot Study.

BACKGROUND: Enteral nutrition (EN) intolerance and delayed gastric emptying are prevalent in pediatric critical illness and limit EN delivery. Gastrointestinal (GI) hormones may be associated with EN intolerance and delayed gastric emptying in this cohort. METHODS: We determined GI hormone levels, time to achieve 50% of EN goal, and gastric emptying in critically ill children. Total amylin, active ghrelin, total glucagon-like peptide-1 (GLP-1), total gastric inhibitory polypeptide, glucagon, and total peptide-YY (PYY) were measured by multiplex assay and cholecystokinin by ELISA. Lower concentrations of acetaminophen at 1 hour (C1h, µg/mL) using the acetaminophen absorption test defined delayed gastric emptying. Correlation, regression analyses, and a principal component analysis were used to examine the association between GI hormones and time to 50% EN goal and C1h. RESULTS: GI hormones were measured in 14 of 21 patients with gastric emptying testing; median age of 11.2 years (6.74-16.3) and 50% male. Increasing hormone levels from GI hormone profile 1 (GLP-1, glucagon, and amylin) correlated with greater time to reach 50% EN goal (R2 = 0.296, P = 0.04). Decreasing hormone levels from GI hormone profile 2 (PYY and ghrelin) correlated with lower C1h and slower gastric emptying (R2 = 0.342, P = 0.02). CONCLUSION: GI hormone profiles are associated with time to achieve 50% of EN goal and gastric emptying in critically ill children. We have described a feasible model to study the role of GI hormones in this cohort, including the potential clinical applicability of GI hormone measurement in the management of delayed gastric emptying.

Differential Metabolomic Signatures in Patients with Weight Regain and Sustained Weight Loss After Gastric Bypass Surgery: A Pilot Study.

BACKGROUND: While Roux-en-Y gastric bypass (RYGB) is one of the most effective and durable treatment options for obesity and its comorbidities, it is complicated by long-term weight regain in over 20% of patients. AIMS: We sought to determine the metabolite signatures of serum samples of patients with weight regain (RYGB-WR) after RYGB and features distinguishing these patients from patients with sustained weight loss (RYGB-SWL). METHODS: We prospectively analyzed serum samples from 21 RYGB-WR patients, 14 RYGB-SWL patients, and 11 unoperated controls. The main outcome measure was their serum metabolite profile. RESULTS: Weight regain after RYGB was associated with a unique serum metabolomic fingerprint. Most of the statistically different metabolites were involved in amino acid metabolism, one-carbon metabolism, and related nucleotide metabolism. A principal component analysis identified groups of metabolites that correlate with weight regain. Specifically, weight regain was associated with lower serum levels of metabolites related to the serine, glycine and threonine pathway, phenylalanine metabolism, tricyclic acid cycle, alanine and glutamate metabolism, and higher levels of other amino acids. CONCLUSIONS: Weight regain after RYGB is associated with unique serum metabolite signatures. Metabolite profiling may eventually help us to identify markers that could differentiate the patients who will regain weight versus those who will likely sustain weight loss.

The Feasibility of Examining the Effects of Gastric Bypass Surgery on Intestinal Metabolism: Prospective, Longitudinal Mechanistic Clinical Trial.

BACKGROUND: Bariatric surgery, especially Roux-en-Y gastric bypass (RYGB), is the best treatment for severe obesity and its complications including type 2 diabetes mellitus (T2DM). Understanding the mechanisms responsible for the beneficial metabolic effects will help to engineer ways to improve the procedure or produce these effects without surgery. OBJECTIVE: The aim is to present data on recruitment and feasibility of a translational study designed to collect intestinal samples before and after bariatric surgery. The goal of biobanking is to allow future studies to test the hypothesis that the mechanism of action of RYGB involves specific changes in the postsurgical short- and long-term metabolism and morphology of the jejunum (Roux limb). Specifically, to test whether the intestine enhances its metabolism and activity after RYGB and increases its fuel utilization, we designed a prospective, longitudinal study, which involved the recruitment of candidates for RYGB with and without T2DM. We describe the tissue bank that we have generated, and our experience, hoping to further facilitate the performance of longitudinal mechanistic studies in human patients undergoing bariatric surgery and especially those involving post-RYGB intestinal biology. METHODS: We conducted a trial to characterize the effects of RYGB on intestinal metabolism. Intestinal tissue samples were collected from the jejunum at surgery, 1, 6, and 12 months postoperatively for the analysis of intestinal gene expression and metabolomic and morphologic changes. The target number of patients who completed at least the 6-month follow-up was 26, and we included a 20% attrition rate, increasing the total number to 32. RESULTS: To enroll 26 patients, we had to approach 79 potential participants. A total of 37 agreed to participate and started the study; 33, 30, and 26 active participants completed their 1-month, 6-month, and 12-month studies, respectively. Three participants withdrew, and 30 participants are still active. Altruism and interest in research were the most common reasons for participation. Important factors for feasibility and successful retention included (1) large volume case flow, (2) inclusion and exclusion criteria broad enough to capture a large segment of the patient population but narrow enough to ensure the completion of study aims and protection of safety concerns, (3) accurate assessment of willingness and motivation to participate in a study, (4) seamless integration of the recruitment process into normal clinical flow, (5) financial reimbursement and nonfinancial rewards and gestures of appreciation, and (6) nonburdensome follow-up visits and measures and reasonable time allotted. CONCLUSIONS: Human translational studies of the intestinal mechanisms of metabolic and weight changes after bariatric surgery are important and feasible. A tissue bank with unique samples has been established that could be used by investigators in many research fields, further enabling mechanistic studies on the effects of bariatric surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT02710370; https://clinicaltrials.gov/ct2/show/NCT02710370 (Archived by WebCite at http://www.webcitation.org/75HrQT8Dl).

Intestine-Specific Overexpression of LDLR Enhances Cholesterol Excretion and Induces Metabolic Changes in Male Mice.

Roux-en-Y gastric bypass (RYGB) surgery is one of the most effective treatment options for severe obesity and related comorbidities, including hyperlipidemia, a well-established risk factor of cardiovascular diseases. Elucidating the molecular mechanisms underlying the beneficial effects of RYGB may facilitate development of equally effective, but less invasive, treatments. Recent studies have revealed that RYGB increases low-density lipoprotein receptor (LDLR) expression in the intestine of rodents. Therefore, in this study we first examined the effects of RYGB on intestinal cholesterol metabolism in human patients, and we show that they also exhibit profound changes and increased LDLR expression. We then hypothesized that the upregulation of intestinal LDLR may be sufficient to decrease circulating cholesterol levels. To this end, we generated and studied mice that overexpress human LDLR specifically in the intestine. This perturbation significantly affected intestinal metabolism, augmented fecal cholesterol excretion, and induced a reciprocal suppression of the machinery related to luminal cholesterol absorption and bile acid synthesis. Circulating cholesterol levels were significantly decreased and, remarkably, several other metabolic effects were similar to those observed in RYGB-treated rodents and patients, including improved glucose metabolism. These data highlight the importance of intestinal cholesterol metabolism for the beneficial metabolic effects of RYGB and for the treatment of hyperlipidemia.

Publisher Correction: Inactivating hepatic follistatin alleviates hyperglycemia.

In the version of this article originally published, the y axis labels in Fig. 4b,d were incorrect. In Fig. 4b, the unit on the label was (ng mg-1). This should have been (ng/ml). In Fig. 4d, the y axis label was Serum Fst (ng ml-1). It should have been Serum insulin (ng/ml). The errors have been corrected in the HTML and PDF versions of this article.

Time-Dependent Molecular Responses Differ between Gastric Bypass and Dieting but Are Conserved Across Species.

The effectiveness of Roux-en-Y gastric bypass (RYGB) against obesity and its comorbidities has generated excitement about developing new, less invasive treatments that use the same molecular mechanisms. Although controversial, RYGB-induced improvement of metabolic function may not depend entirely upon weight loss. To elucidate the differences between RYGB and dieting, we studied several individual organ molecular responses and generated an integrative, interorgan view of organismal physiology. We also compared murine and human molecular signatures. We show that, although dieting and RYGB can bring about the same degree of weight loss, post-RYGB physiology is very different. RYGB induces distinct, organ-specific adaptations in a temporal pattern that is characterized by energetically demanding processes, which may be coordinated by HIF1a activation and the systemic repression of growth hormone receptor signaling. Many of these responses are conserved in rodents and humans and may contribute to the remarkable ability of surgery to induce and sustain metabolic improvement.

Inactivating hepatic follistatin alleviates hyperglycemia.

Unsuppressed hepatic glucose production (HGP) contributes substantially to glucose intolerance and diabetes, which can be modeled by the genetic inactivation of hepatic insulin receptor substrate 1 (Irs1) and Irs2 (LDKO mice). We previously showed that glucose intolerance in LDKO mice is resolved by hepatic inactivation of the transcription factor FoxO1 (that is, LTKO mice)-even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue of LDKO mice is also impaired but is restored in LTKO mice in conjunction with normal suppression of HGP by insulin. To establish the mechanism by which white adipose tissue insulin signaling and HGP was regulated by hepatic FoxO1, we identified putative hepatokines-including excess follistatin (Fst)-that were dysregulated in LDKO mice but normalized in LTKO mice. Knockdown of hepatic Fst in the LDKO mouse liver restored glucose tolerance, white adipose tissue insulin signaling and the suppression of HGP by insulin; however, the expression of Fst in the liver of healthy LTKO mice had the opposite effect. Of potential clinical significance, knockdown of Fst also improved glucose tolerance in high-fat-fed obese mice, and the level of serum Fst was reduced in parallel with glycated hemoglobin in obese individuals with diabetes who underwent therapeutic gastric bypass surgery. We conclude that Fst is a pathological hepatokine that might be targeted for diabetes therapy during hepatic insulin resistance.

Nonalcoholic fatty liver disease and gastric bypass surgery regulate serum and hepatic levels of pyruvate kinase isoenzyme M2.

Treatment of nonalcoholic fatty liver disease (NAFLD) focuses on the underlying metabolic syndrome, and Roux-en-Y gastric bypass surgery (RYGB) remains one of the most effective options. In rodents and human patients, RYGB induces an increase in the gene and protein expression levels of the M2 isoenzyme of pyruvate kinase (PKM2) in the jejunum. Since PKM2 can be secreted in the circulation, our hypothesis was that the circulating levels of PKM2 increase after RYGB. Our data, however, revealed an unexpected finding and a potential new role of PKM2 for the natural history of metabolic syndrome and NAFLD. Contrary to our initial hypothesis, RYGB-treated patients had decreased PKM2 blood levels compared with a well-matched group of patients with severe obesity before RYGB. Interestingly, PKM2 serum concentration correlated with body mass index before but not after the surgery. This prompted us to evaluate other potential mechanisms and sites of PKM2 regulation by the metabolic syndrome and RYGB. We found that in patients with NAFLD and nonalcoholic steatohepatitis (NASH), the liver had increased PKM2 expression levels, and the enzyme appears to be specifically localized in Kupffer cells. The study of murine models of metabolic syndrome and NASH replicated this pattern of expression, further suggesting a metabolic link between hepatic PKM2 and NAFLD. Therefore, we conclude that PKM2 serum and hepatic levels increase in both metabolic syndrome and NAFLD and decrease after RYGB. Thus, PKM2 may represent a new target for monitoring and treatment of NAFLD.

Critical role for arginase 2 in obesity-associated pancreatic cancer.

Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDA remain unknown. Here we show that obesity-driven PDA exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDA. In vivo infusion of 15N-glutamine in obese mouse models of PDA demonstrates enhanced nitrogen flux into the urea cycle and infusion of 15N-arginine shows that Arg2 loss causes significant ammonia accumulation that results from the shunting of arginine catabolism into alternative nitrogen repositories. Furthermore, analysis of PDA patient tumors indicates that ARG2 levels correlate with body mass index (BMI). The specific dependency of PDA on ARG2 rather than the principal hepatic enzyme ARG1 opens a therapeutic window for obesity-associated pancreatic cancer.Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Here the authors show that obesity induces the expression of the mitochondrial form of arginase ARG2 in PDA and that ARG2 silencing or loss results in ammonia accumulation and suppression of obesity-driven PDA tumor growth.

Reversible hyperphagia and obesity in rats with gastric bypass by central MC3/4R blockade.

OBJECTIVE: To test the commonly held assumption that gastric bypass surgery lowers body weight because it limits the ability to eat large amounts of food. METHODS: Central melanocortin signaling was blocked by ICV infusion of the melanocortin-3/4 receptor antagonist SHU9119 for 14 days in rats whose high-fat diet-induced obesity had been reversed by Roux-en-Y gastric bypass surgery. RESULTS: SHU9119 increased daily food intake (+ 100%), body weight (+30%), and fat mass (+50%) in rats with RYGB, surpassing the presurgical body weight and that of saline-treated sham-operated rats. Doubling of food intake was entirely due to increased meal frequency, but not meal size. After termination of SHU9119, body weight promptly returned to near preinfusion levels. In sham-operated rats, SHU9119 produced even larger increases in food intake and body weight. CONCLUSIONS: RYGB rats do not settle at a lower level of body weight because they cannot eat more food as they can easily double food intake by increasing meal frequency. The reversible obesity suggests that RYGB rats actively defend the lower body weight. However, because both RYGB and sham-operated rats responded to SHU9119, central melanocortin signaling is not the critical mechanism in RYGB rats responsible for this defense.

GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents.

Exaggerated GLP-1 and PYY secretion is thought to be a major mechanism in the reduced food intake and body weight after Roux-en-Y gastric bypass surgery. Here, we use complementary pharmacological and genetic loss-of-function approaches to test the role of increased signaling by these gut hormones in high-fat diet-induced obese rodents. Chronic brain infusion of a supramaximal dose of the selective GLP-1 receptor antagonist exendin-9-39 into the lateral cerebral ventricle significantly increased food intake and body weight in both RYGB and sham-operated rats, suggesting that, while contributing to the physiological control of food intake and body weight, central GLP-1 receptor signaling tone is not the critical mechanism uniquely responsible for the body weight-lowering effects of RYGB. Central infusion of the selective Y2R-antagonist BIIE0246 had no effect in either group, suggesting that it is not critical for the effects of RYGB on body weight under the conditions tested. In a recently established mouse model of RYGB that closely mimics surgery and weight loss dynamics in humans, obese GLP-1R-deficient mice lost the same amount of body weight and fat mass and maintained similarly lower body weight compared with wild-type mice. Together, the results surprisingly provide no support for important individual roles of either gut hormone in the specific mechanisms by which RYGB rats settle at a lower body weight. It is likely that the beneficial effects of bariatric surgeries are expressed through complex mechanisms that require combination approaches for their identification.

Reprogramming of intestinal glucose metabolism and glycemic control in rats after gastric bypass.

The resolution of type 2 diabetes after Roux-en-Y gastric bypass (RYGB) attests to the important role of the gastrointestinal tract in glucose homeostasis. Previous studies in RYGB-treated rats have shown that the Roux limb displays hyperplasia and hypertrophy. Here, we report that the Roux limb of RYGB-treated rats exhibits reprogramming of intestinal glucose metabolism to meet its increased bioenergetic demands; glucose transporter-1 is up-regulated, basolateral glucose uptake is enhanced, aerobic glycolysis is augmented, and glucose is directed toward metabolic pathways that support tissue growth. We show that reprogramming of intestinal glucose metabolism is triggered by the exposure of the Roux limb to undigested nutrients. We demonstrate by positron emission tomography-computed tomography scanning and biodistribution analysis using 2-deoxy-2-[18F]fluoro-D-glucose that reprogramming of intestinal glucose metabolism renders the intestine a major tissue for glucose disposal, contributing to the improvement in glycemic control after RYGB.

Probing the mechanisms of the metabolic effects of weight loss surgery in humans using a novel mouse model system.

BACKGROUND: Gastrointestinal weight loss surgery, especially Roux-en-Y gastric bypass (RYGB), is the most effective treatment for severe obesity. RYGB is associated with a remarkable decrease in the rate of death from obesity-related complications, such as diabetes mellitus, coronary artery disease, and cancer. Dissecting the mechanisms of RYGB effects could augment our understanding about the pathogenesis of obesity and its complications. OBJECTIVES AND METHODS: In this study, we describe in detail a mouse model of RYGB that closely reproduces the surgical steps of the human procedure. RESULTS: We show that RYGB in mice has the same effects as in human patients, proving the high translational validity of this model system. We present an intraoperative video to facilitate the widespread use of this complex and difficult method. CONCLUSIONS: The study of the mechanisms of RYGB using this model system can greatly facilitate our understanding about the effects of RYGB in human patients. The reverse engineering of the physiological mechanisms of RYGB could lead to discovery of new, effective, and less invasive treatments.

Isolated duodenal exclusion increases energy expenditure and improves glucose homeostasis in diet-induced obese rats.

Roux-en-Y gastric bypass (RYGB) in rodent models reduces food intake (FI), increases resting energy expenditure (EE), and improves glycemic control. We have shown that mimicking the duodenal component of RYGB by implantation of a 10-cm endoluminal sleeve device (ELS-10) induces weight loss and improves glycemic control in diet-induced obese (DIO) rats. We sought to determine the mechanisms and structural requirements of these effects. We examined the effects of ELS-10 devices implanted in male DIO rats on body weight, food intake (FI), meal patterns, total and resting EE, and multiple parameters of glucose homeostasis, comparing them with sham-operated (SO) rats and with SO rats weight matched to the ELS-10-treated group. To determine the extent of duodenal exclusion required to influence metabolic outcomes, we compared the effects of implanting 10-, 4-, or 1-cm ELS devices. ELS-10 rats exhibited 13% higher total and 9% higher resting EE than SO controls. ELS-10 rats also exhibited enhanced postprandial GLP-1 secretion and improved glucose tolerance and insulin sensitivity out of proportion to the effects of weight loss alone. Implantation of 4- or 1-cm ELS devices had no effect on EE and limited effects on glucose homeostasis. Complete duodenal exclusion with ELS-10 induces weight loss by decreasing FI and increasing EE and improves glycemic control through weight loss-independent mechanisms. Thus signals originating in the proximal small intestine appear to exert a direct influence on the physiological regulation of EE and glucose homeostasis. Their selective manipulation could provide effective new therapies for obesity and diabetes that mimic the benefits of RYGB.

Melanocortin-4 receptor signaling is required for weight loss after gastric bypass surgery.

CONTEXT: Roux-en-Y gastric bypass (RYGB) is one of the most effective long-term therapies for the treatment of severe obesity. Recent evidence indicates that RYGB effects weight loss through multiple physiological mechanisms, including changes in energy expenditure, food intake, food preference, and reward pathways. OBJECTIVE: Because central melanocortin signaling plays an important role in the regulation of energy homeostasis, we investigated whether genetic disruption of the melanocortin-4 receptor (MC4R) in rodents and humans affects weight loss after RYGB. METHODS AND RESULTS: Here we report that MC4R(-/-) mice lost substantially less weight after surgery than wild-type animals, indicating that MC4R signaling is necessary for the weight loss effects of RYGB in this model. Mice heterozygous for MC4R remain fully responsive to gastric bypass. To determine whether mutations affect surgically induced weight loss in humans, we sequenced the MC4R gene in 972 patients undergoing RYGB. Patients heterozygous for MC4R mutations exhibited the same magnitude and distribution of postoperative weight loss as patients without such mutations, suggesting that although two normal copies of the MC4R gene are necessary for normal weight regulation, a single normal copy of the MC4R gene is sufficient to mediate the weight loss effects of RYGB. CONCLUSIONS: MC4R is the first gene identified that is required for the sustained effects of bariatric surgery. The need for MC4R signaling for the weight loss effects of RYGB in mice underscores the physiological mechanisms of action of this procedure and demonstrates that RYGB both influences and is dependent on the normal pathways that regulate energy balance.