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

Abstract

-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...

Bariatric surgery and obesity: influence on the incretins

“…6 Lessons from rodent models Although data in humans and pigs support a role for GLP-1 in controlling glucose metabolism after RYGBP, experiments with knock-out animal models challenge the role of GLP-1 in the control of body weight and glucose after RYGBP or vertical sleeve gastrectomy (VSG). Berthoud et al 59 showed that 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 after a RYGBP-like procedure. 59 GLP-1 levels are also enhanced after VSG in humans 60 and rodents, 61 and are thought to be a mediator of diabetes remission after this surgery.…”

“…Berthoud et al 59 showed that 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 after a RYGBP-like procedure. 59 GLP-1 levels are also enhanced after VSG in humans 60 and rodents, 61 and are thought to be a mediator of diabetes remission after this surgery. 62 However, VSG-operated GLP-1R-deficient mice respond similarly to wild-type controls in terms of body weight loss, improved glucose tolerance, food intake reduction, and altered food selection.…”

Does gastric bypass surgery change body weight set point?

“…51 However, subsequent studies in rodents directly testing roles for each of these gut hormones in the beneficial effects of RYGB and sleeve gastrectomy were largely negative. Neither GLP-1 receptor deficiency nor ghrelin deficiency appreciably changed the effects of RYGB 17,52 or sleeve gastrectomy, 53,54 and neither GLP-1 receptor nor PYY/Y2 receptor blockade in the brain attenuated RYGB-induced body weight suppression 17 (but see Chandarana et al 55 for a different outcome). Although these studies do not lend much support for individual roles of these hormones, it is possible that they act synergistically.…”

“…Consistent with our findings, transient hyperphagia and weight gain was also observed in female rats with sleeve gastrectomy during pregnancy and lactation. 15 In our mouse RYGB model, 16,17 we used a different approach, in that we lowered pre-surgical body weight by calorie-restriction before RYGB surgery. After 12 weeks on high-fat diet, mice weighed about 35 g, 12 g of which was fat mass.…”

Biologic Responses to Weight Loss and Weight Regain: Report From an American Diabetes Association Research Symposium

“…Many investigators have suggested that GLP-1 may play a role. However, in rat studies, blocking GLP-1 does not affect the response to RYGB (84). Peptide YY knockout mice do not significantly decrease body weight after bypass surgery (85), suggesting that the hormone has some role in RYGB benefits.…”