Peripheral, but not central, GLP-1 receptor signaling is required for improvement in glucose tolerance after Roux-en-Y gastric bypass in mice

Abstract

Carmody JS, Muñoz R, Yin H, Kaplan LM. Peripheral, but not central, GLP-1 receptor signaling is required for improvement in glucose tolerance after Roux-en-Y gastric bypass in mice. Am J Physiol Endocrinol Metab 310: E855-E861, 2016. First published March 29, 2016; doi:10.1152/ajpendo.00412.2015.-Roux-en-Y gastric bypass (RYGB) causes profound weight loss and remission of diabetes by influencing metabolic physiology, yet the mechanisms behind these clinical improvements remain undefined. After RYGB, levels of glucagon-like peptide-1 (GLP-1), a hormone that enhances insulin secretion and promotes satiation, are substantially elevated. Because GLP-1 signals in both the periphery and the brain to influence energy balance and glucose regulation, we aimed to determine the relative requirements of these systems to weight loss and improved glucose tolerance following RYGB surgery in mice. By pharmacologically blocking peripheral or central GLP-1R signaling, we examined whether GLP-1 action is necessary for the metabolic improvements observed after RYGB. Diet-induced obese mice underwent RYGB or sham operation and were implanted with osmotic pumps delivering the GLP-1R antagonist exendin-(9 -39) (2 pmol·kg Ϫ1 ·min Ϫ1 peripherally; 0.5 pmol·kg Ϫ1 ·min Ϫ1 centrally) for up to 10 wk. Blockade of peripheral GLP-1R signaling partially reversed the improvement in glucose tolerance after RYGB. In contrast, fasting glucose and insulin sensitivity, as well as body weight, were unaffected by GLP-1R antagonism. Central GLP-1R signaling did not appear to be required for any of the metabolic improvements seen after this operation. Collectively, these results suggest a detectable but only modest role for GLP-1 in mediating the effects of RYGB and that this role is limited to its well-described action on glucose regulation.glucagon-like peptide-1; Roux-en-Y gastric bypass; glucose tolerance; obesity; central regulation THE HIGH PREVALENCE OF OBESITY and its related comorbidities, including type 2 diabetes mellitus (T2DM), underscores the need for effective weight loss treatments. Conventional therapies to treat obesity, including behavioral modification relating to diet and exercise, often yield only short-term benefits, whereas gastrointestinal weight loss operations such as Rouxen-Y gastric bypass (RYGB) have been effective in producing long-term weight loss and remission of diabetes in most patients (2). RYGB operations convey these metabolic improvements by influencing the physiology of energy balance and glucose regulation that is disordered in obesity and diabetes, respectively. The rapid and profound improvement in glucose regulation following RYGB suggests the stimulation of weight-independent effects of the surgery, although the precise mechanisms of these effects have only begun to be elucidated (21, 25).Physiologically, RYGB initiates changes in the secretion and circulation of numerous hormones, including peptide YY (PYY), insulin, amylin, and glucagon-like peptide-1 (GLP-1) in directions that suggest their contribution to...

Effects of Obesity and Gastric Bypass Surgery on Nutrient Sensors, Endocrine Cells, and Mucosal Innervation of the Mouse Colon

“…Unchanged GLP-1R expression in colonic mucosa agrees with our previous work as well as others showing GLP-1R is not required for the beneficial effects of RYGB [ 39 , 40 ]. However, GLP-1 acting on GLP-1R expressed on pancreatic β-cells is required for partial improvement of glucose tolerance after RYGB in mice [ 41 ].…”

Plasticity of gastrointestinal vagal afferent satiety signals

“…In addition, it has been demonstrated that obese mice do not increase food intake in response to a GLP‐1 antagonist, extendin‐9, suggesting a degree of insensitivity to the anorexigenic effect of GLP‐1 in obesity. Interestingly, other effects of GLP‐1 such as regulation of blood glucose levels appear to be maintained . However, the GLP‐1 analog liragluteride in addition to improving insulin sensitivity also leads to weight loss in humans .…”

“…Interestingly, other effects of GLP-1 such as regulation of blood glucose levels appear to be maintained. 123 However, the GLP-1 analog liragluteride in addition to improving insulin sensitivity also leads to weight loss in humans. 124 Administration of the GLP-1 agonist exendin-4 has been shown to reduce food intake in obese DIO-P rats, but by a smaller amount than DIO-R rats.…”

Changes in gut hormones, glycaemic response and symptoms after oesophagectomy

“…On the other hand, meal termination and satiety are mediated by secretion of anorectic gut hormones such as glucagon‐like peptide (GLP) 1, which are secreted by enteroendocrine cells of the small and large intestine following direct interaction of ingested nutrients with taste and fatty acid receptors on their luminal surfaces. Importantly, GLP‐1 and other gut peptides also serve to enhance postprandial nutrient utilization, through both stimulation of insulin secretion and increased peripheral insulin sensitivity.…”