Glucagon-like peptide 1 receptors (GLP-1R) are expressed in multiple tissues and activation results in metabolic benefits including enhanced insulin secretion, slowed gastric emptying, suppressed food intake, and improved hepatic steatosis. Limited and inconclusive knowledge exists regarding whether the effects of chronic exposure to a GLP-1R agonist are solely mediated via this receptor. Therefore, we examined 3-mo dosing of exenatide in mice lacking a functional GLP-1R (Glp1r^−/−). Exenatide (30 nmol·kg⁻¹·day⁻¹) was infused subcutaneously for 12 wk in Glp1r^−/− and wild-type (Glp1r^+/+) control mice fed a high-fat diet. Glycated hemoglobin A1c (HbA1c), plasma glucose, insulin, amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), body weight, food intake, terminal hepatic lipid content (HLC), and plasma exenatide levels were measured. At the end of the study, oral glucose tolerance test (OGTT) and rate of gastric emptying were assessed. Exenatide produced no significant changes in Glp1r^−/− mice at study end. In contrast, exenatide decreased body weight, food intake, and glucose in Glp1r^+/+ mice. When compared with vehicle, exenatide reduced insulin, OGTT glucose AUC_0–2h, ALT, and HLC in Glp1r^+/+ mice. Exenatide had no effect on plasma amylase or lipase levels. Exenatide concentrations were approximately eightfold higher in Glp1r^−/− versus Glp1r^+/+ mice after 12 wk of infusion, whereas renal function was similar. These data support the concept that exenatide requires a functional GLP-1R to exert chronic metabolic effects in mice, and that novel “GLP-1” receptors may not substantially contribute to these changes. Differential exenatide plasma levels in Glp1r^+/+ versus Glp1r^−/− mice suggest that GLP-1R may play an important role in plasma clearance of exenatide and potentially other GLP-1-related peptides.