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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 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.

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.