exendin-(9-39) and Weight-Loss

Bariatric surgery is an effective intervention for management of obesity through treating dysregulated appetite and achieving long-term weight loss maintenance. Moreover, significant changes in glucose homeostasis are observed after bariatric surgery including, in some cases, type 2 diabetes remission from the early postoperative period and postprandial hypoglycaemia. Levels of a number of gut hormones are dramatically increased from the early period after Roux-en-Y gastric bypass and sleeve gastrectomy-the two most commonly performed bariatric procedures-and they have been suggested as important mediators of the observed changes in eating behaviour and glucose homeostasis postoperatively. In this review, we summarise the current evidence from human studies on the alterations of gut hormones after bariatric surgery and their impact on clinical outcomes postoperatively. Studies which assess the role of gut hormones after bariatric surgery on food intake, hunger, satiety and glucose homeostasis through octreotide use (a non-specific inhibitor of gut hormone secretion) as well as with exendin 9-39 (a specific glucagon-like peptide-1 receptor antagonist) are reviewed. The potential use of gut hormones as biomarkers of successful outcomes of bariatric surgery is also evaluated.

Topics: Adult; Bariatric Surgery; Biomarkers; Blood Glucose; Combined Modality Therapy; Eating; Female; Gastrectomy; Gastric Bypass; Gastrointestinal Hormones; Humans; Hunger; Male; Middle Aged; Obesity, Morbid; Octreotide; Peptide Fragments; Postoperative Period; Satiation; Treatment Outcome; Weight Loss

Bariatric surgery is the most effective treatment for obesity and diabetes. The 2 most commonly performed weight-loss procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy, improve glycemic control in patients with type 2 diabetes independent of weight loss. One of the early hypotheses raised to explain the immediate antidiabetic effect of RYGB was that rapid delivery of nutrients from the stomach pouch into the distal small intestine enhances enteroinsular signaling to promote insulin signaling. Given the tenfold increase in postmeal glucagon-like peptide-1 (GLP-1) response compared to unchanged integrated levels of postprandial glucose-dependent insulinotropic peptide after RYGB, enhanced meal-induced insulin secretion after this procedure was thought to be the result of elevated glucose and GLP-1 levels. In this contribution to the larger point-counterpoint debate about the role of GLP-1 after bariatric surgery, most of the focus will be on RYGB.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Peptide Fragments; Postprandial Period; Weight Loss

Exaggerated postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) may explain appetite reduction and weight loss after Roux-en-Y gastric bypass (RYGB), but causality has not been established. We hypothesized that food intake decreases after surgery through combined actions from GLP-1 and PYY. GLP-1 actions can be blocked using the GLP-1 receptor antagonist Exendin 9-39 (Ex-9), whereas PYY actions can be inhibited by the administration of a dipeptidyl peptidase-4 (DPP-4) inhibitor preventing the formation of PYY. In study 1, food intake decreased by 35% following RYGB compared with before surgery. Before surgery, GLP-1 receptor blockage increased food intake but no effect was seen postoperatively, whereas PYY secretion was markedly increased. In study 2, combined GLP-1 receptor blockage and DPP-4 inhibitor mediated lowering of PYY. Blockade of actions from only one of the two L-cell hormones, GLP-1 and PYY

Topics: Appetite; Appetite Regulation; Cross-Over Studies; Denmark; Diabetes Mellitus, Type 2; Eating; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Male; Obesity, Morbid; Peptide Fragments; Peptide YY; Treatment Outcome; Weight Loss

Topics: Adult; Bariatric Surgery; Body Composition; Case-Control Studies; Female; Gastrectomy; Gastric Bypass; Gastric Emptying; Gastrointestinal Hormones; Glucagon-Like Peptide-1 Receptor; Humans; Insulin; Male; Middle Aged; Obesity; Peptide Fragments; Pilot Projects; Postprandial Period; Weight Loss

The overlap in neurobiological circuitry mediating the physiological and behavioral response to satiation and noxious/stressful stimuli are not well understood. The interaction between serotonin (5-HT) and glucagon-like peptide-1 (GLP-1) could play a role as upstream effectors involved in mediating associations between anorectic and noxious/stressful stimuli. We hypothesize that 5-HT acts as an endogenous modulator of the central GLP-1 system to mediate satiation and malaise in rats. Here, we investigate whether interactions between central 5-HT and GLP-1 signaling are behaviorally and physiologically relevant for the control of food intake and pica (i.e., behavioral measure of malaise). Results show that the anorexia and body weight changes induced by administration of exogenous hindbrain 5-HT are dependent on central GLP-1 receptor signaling. Furthermore, anatomical evidence shows mRNA expression of 5-HT2C and 5-HT3 receptors on GLP-1-producing preproglucagon (PPG) neurons in the medial nucleus tractus solitarius by fluorescent in situ hybridization, suggesting that PPG neurons are likely to express both of these receptors. Behaviorally, the hypophagia induced by the pharmacological activation of both of these receptors is also dependent on GLP-1 signaling. Finally, 5-HT3, but not 5-HT2C receptors, are required for the anorectic effects of the interoceptive stressor LiCl, suggesting the hypophagia induced by these 5-HT receptors may be driven by different mechanisms. Our findings highlight 5-HT as a novel endogenous modulator of the central GLP-1 system and suggest that the central interaction between 5-HT and GLP-1 is involved in the control of food intake in rats.

Topics: Animals; Anorexia; Feeding Behavior; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Lithium Chloride; Male; Neurons; Ondansetron; Peptide Fragments; Pica; Proglucagon; Rats; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin, 5-HT3; Rhombencephalon; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT3 Receptor Agonists; Serotonin 5-HT3 Receptor Antagonists; Signal Transduction; Solitary Nucleus; Stress, Psychological; Weight Loss

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.

Topics: Animals; Arginine; Benzazepines; Body Composition; Body Weight; Dietary Fats; Eating; Energy Metabolism; Gastric Bypass; Glucagon-Like Peptide-1 Receptor; Male; Mice; Mice, Knockout; Motor Activity; Obesity; Oxygen Consumption; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Weight Loss