-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...

Background Roux-en-Y gastric bypass (RYGB) surgery is very effective in reducing excess body weight and improving glucose homeostasis in obese subjects. Changes in the pattern of gut hormone secretion are thought to play a major role, but the mechanisms leading to both changed hormone secretion and beneficial effects remain unclear. Specifically, it is not clear whether changes in the number of hormone-secreting enteroendocrine cells, or changes in the releasing stimuli, or both, are important. Methods We estimated numbers of enteroendocrine cells after immunohistochemical staining in fixed tissue samples from rats at 10–11 months after RYGB. Key Results Numbers of glucagon-like peptide-1 (GLP-1) (L-cells, co-expressing peptide YY (PYY)), cholecystokinin (CCK), neurotensin, and 5-HT-immunoreactive cells were significantly increased in the Roux and common limbs, but not the biliopancreatic limb in RYGB rats compared with sham-operated, obese rats fed high-fat diet, and chow-fed controls. This increase was mostly accounted for by general hyperplasia of all intestinal wall layers of the nutrient-perfused Roux and common limbs, and less to increased density of expression. The number of ghrelin cells in the bypassed stomach was not different among the three groups. Conclusions & Inferences The findings suggest that the number of enteroendocrine cells increases passively as the gut adapts, and that the increased total number of L- and I-cells is likely to contribute to the higher circulating levels of GLP-1, PYY, and CCK, potentially leading to suppression of food intake and stimulation of insulin secretion. Whether changes in releasing stimuli also contribute to altered circulating levels will have to be determined in future studies.

Background The mechanisms by which Roux-en-Y gastric bypass surgery (RYGB) so effectively lowers body weight and improves glycemic control are not well understood and murine models are essential for identifying the crucial signaling pathways involved. Aims To characterize the time course of RYGB on body weight, body composition, food intake, and energy expenditure in diet-induced obese mice, and establish a tissue bank for global “omics” or targeted biochemical and structural analyses. Methods High-fat diet-induced obese mice were subjected to RYGB using an improved surgical technique with a small gastric pouch. The effects on body weight, body composition, food intake, and energy expenditure were compared to sham surgery, high-fat diet-restricted weight-matched controls, and never obese chow-fed controls. Results Without mortality or complications, RYGB surgery in high-fat diet-induced obese mice gradually decreased body weight to a plateau that was more or less sustained for up to 12 weeks (33 g, −18%, p<0.01) and significantly lower compared with sham-operated mice (51 g, +25%, p <0.01), but higher (+18%, p<0.01) than age-matched, chow-fed control mice (27 g). Energy intake after RYGB was significantly suppressed compared to sham only for the first 10 days, but significantly higher compared to weight-matched mice. Energy expenditure after RYGB was higher throughout the study compared with weight-matched, but not sham animals. Conclusions RYGB surgery in diet-induced obese mice results in similar body weight and body composition changes as observed in humans, but in contrast to humans, this is achieved mainly through increased energy expenditure rather than decreased food intake.