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.

ObjectiveTo examine the hypothesis that elective laparoscopic repair should be routinely performed on patients with asymptomatic or minimally symptomatic paraesophageal hernias. Summary Background DataThe management of asymptomatic paraesophageal hernias is a controversial issue. Most surgeons believe that all paraesophageal hernias should be corrected electively on diagnosis, irrespective of symptoms, to prevent the development of complications and avoid the risk of emergency surgery. MethodsA Markov Monte Carlo decision analytic model was developed to track a hypothetical cohort of patients with asymptomatic or minimally symptomatic paraesophageal hernia and reflect the possible clinical outcomes associated with two treatment strategies: elective laparoscopic paraesophageal hernia repair (ELHR) or watchful waiting (WW). The input variables for ELHR were estimated from a pooled analysis of 20 published studies, while those for WW and emergency surgery were derived from the 1997 HCUP-NIS database and surgical literature published from 1964 to 2000. Outcomes for the two strategies were expressed in quality-adjusted lifeyears (QALYs). ResultsAnalysis of the HCUP-NIS database showed that published studies overestimate the mortality of emergency surgery (17% vs. 5.4%). The mortality rate of ELHR was 1.4%. The annual probability of developing acute symptoms requiring emergency surgery with the WW strategy was 1.1%. For patients 65 years of age, ELHR resulted in reduction of 0.13 QALYs (10.78 vs. 10.65) compared with WW. The model predicted that WW was the optimal treatment strategy in 83% of patients and ELHR in the remaining 17%. The model was sensitive only to alterations of the mortality rates of ELHR and emergency surgery. ConclusionsIf ELHR is routinely recommended, it would be more beneficial than WW in fewer than one of five patients. WW is a reasonable alternative for the initial management of patients with asymptomatic or minimally symptomatic paraesophageal hernias, and even if an emergency operation is required, the burden of the procedure is not as severe as was thought in the past.The need for surgical correction of asymptomatic paraesophageal hernias is controversial. Many surgeons, citing the influential studies of Belsey 1 and Hill, 2 advocate elective repair of all paraesophageal hernias irrespective of symptoms. The rationale for this approach is prophylactic; that is, prevention of life-threatening complications such as obstruction and strangulation and avoidance of the significant morbidity and mortality of an emergency operation. The perception that laparoscopic techniques offer a less morbid approach to surgical correction of paraesophageal hernias is cited as an additional reason to support the elective repair of paraesophageal hernias. However, beliefs held by the surgical community about the natural history of paraesophageal hernias and the morbidity and mortality of both elective and emergency operations are based on relatively small patient series and anecdotal case reports. Several recent ...

Gastrointestinal weight-loss surgery (GIWLS) is currently the most effective treatment for severe obesity, with Roux-en-Y gastric bypass (RYGB) among the best of the available surgical options. Despite its widespread clinical use, the mechanisms by which RYGB induces its profound weight loss remain largely unknown. This procedure effects weight loss by altering the physiology of weight regulation and eating behavior rather than by simple mechanical restriction and/or malabsorption as previously thought. To study how RYGB affects the physiology of energy balance, we developed a rat model of this procedure. In this report, we demonstrate that RYGB in diet-induced obese (DIO) rats induces a 25% weight loss, prolongs mean survival by 45%, and normalizes glucose homeostasis and lipid metabolism. RYGB induced a 19% increase in total and a 31% increase in resting energy expenditure (REE). These effects, along with a 17% decrease in food intake and a 4% decrease in nutrient absorption account for the normalization of body weight after this procedure. These effects indicate that surgery acts by altering the physiology of weight regulation and help to explain the effectiveness of RYGB in comparison to restrictive dieting and other forms of dietary and pharmacological therapies for obesity. The clinical effectiveness of RYGB and its physiological effects on body weight regulation and energy expenditure (EE) suggest that this operation provides a unique opportunity to explore the mechanisms of energy homeostasis and to identify novel therapies for obesity and related metabolic diseases.

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-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 weightlowering 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.Roux-en-Y gastric bypass; gut hormones; brain; GLP-1R knockout; food intake; exendin-(9 -39), BIIE0246; high-fat diet THE NUMBER OF BARIATRIC SURGERIES performed has steadily increased because for many obese patients, it is the last hope for significant and enduring body weight loss and general improvement of health. There have been an increasing number of clinical and preclinical studies with the goal to unravel the mechanisms underlying these beneficial effects of bariatric surgeries, but there has not yet been a breakthrough. A major hypothesis is that changes in gut hormone release are crucial. Drastically increased postprandial circulating levels of GLP-1 and PYY have been demonstrated in clinical studies (18,32,33,36,38,44,47,50) and in rodent models (13, 16, 37, 56) for both Roux-en-Y gastric bypass and vertical sleeve gastrectomy.GLP-1 is a powerful hormone that acts both in the periphery and brain to stimulate insulin secretion, inhibit gastric emptying, and suppress food intake (for recent reviews, see Refs. 7,12,43). Exogenous administration of GLP-1 or its stable analog exendin-4, as well as PYY(3-36), has been shown in numerous preclinical and clinical studies to suppress food intake and lower body weight (e.g., (2,4,5,9,15,19,24,27,40,57,59) or to suppress hepatic glucose production (52), in some of them by directly acting on the brain. The stable GLP-1 receptor agonist exendin-4 is widely used by Type 2 diabetic patients to sta...

Unsuppressed hepatic glucose production (HGP) contributes significantly to glucose intolerance and diabetes, which can be modeled by genetic inactivation of hepatic insulin receptor substrate (Irs) 1 and Irs2 (LDKO-mice). We previously showed that glucose intolerance in LDKO-mice is resolved by hepatic inactivation of the transcription factor FoxO1 (i.e., LTKO-mice)—even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue (WAT) 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 WAT insulin signaling and HGP were 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-liver restored glucose tolerance, WAT insulin signaling, and the suppression of HGP by insulin; however, 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 serum FST was reduced in parallel with glycated hemoglobin in obese individuals with diabetes who underwent therapeutic gastric bypass surgery. We conclude that follistatin is a pathological hepatokine that might be targeted for diabetes therapy during hepatic insulin resistance.

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.

Although the prevalence of obesity has increased dramatically throughout the world during the last 25 yr, its long-term control remains poor. Currently, only gastrointestinal weight loss surgery, especially Roux-en-Y gastric bypass (RYGB), is associated with substantial and sustained weight loss and resolution or significant improvement of diabetes mellitus and other metabolic obesity-induced complications. Clinical observations and recent studies have suggested that RYGB induces its effects by changing the physiology of weight regulation. Understanding the underlying mechanisms of these profound and sustainable effects could facilitate the development of novel and less invasive treatments against obesity and its complications. To study the physiological mechanisms of RYGB, we have developed a mouse RYGB model that replicates the human operation. The aims of this study were to develop a roadmap for assessing energy expenditure (EE) in animal models of weight loss surgery and to examine the effects of RYGB on EE. We first measured EE by indirect calorimetry in groups of animals that underwent RYGB or a sham operation. Calorimetry data were analyzed using three different methods: normalization by total body mass, allometric scaling, and analysis of covariance modeling. RYGB in mice induced a significant increase in EE that was independent of the method used. An energy balance analysis was then performed, which also confirmed that RYGB-treated animals have higher energy maintenance needs. Finally, we determined the EE components that account for the observed increase in EE, and we found that resting EE and postprandial thermogenesis are the major contributors to this increase.