Enteroendocrine L-cells release GLP-1 in response to luminal nutrient (primarily carbohydrate and fat) stimulation. Peripheral and central administration of GLP-1 inhibits eating, and peripheral GLP-1 inhibits gastric emptying (GE) and enhances glucose-induced insulin release. GLP-1 receptors (GLP-1R) are expressed in the periphery and in several brain areas implicated in eating and metabolic control, but the sites and mechanism through which intestinal endogenous GLP-1 exerts its effects are uncertain. Previous studies from our laboratory demonstrated that intact vagal afferent neurons (VAN) are required for the satiating effect of intraperitoneally (IP) administered GLP-1. To address the role of VAN GLP-1R, we knocked down the expression of VAN GLP-1R by bilateral nodose ganglion injection of lentiviral GLP-1R shRNA in male Sprague-Dawley rats. GLP-1R KD in chow-fed rats did not affect the body weight and 24 h cumulative food intake compared to control animals, but it increased meal size, decreased meal frequency, enhanced GE, and postprandial glycemia, indicating that these effects are due to a paracrine effect of endogenous GLP-1 on abdominal VAN. Moreover, GLP-1R KD blunted the satiating and GE inhibitory effects of GLP-1 after IP, but not ICV (4th ventricle) administration. Surprisingly, GLP-1R KD rats fed a high-fat diet (HFD) showed decreased body weight gain, improved glycemic control and increased energy expenditure compared to control animals. This appeared to be related to an increased brown adipose tissue (BAT) UCP1 expression and enhanced sympathetic input to interscapular BAT. Finally, whereas GLP-1R KD decreased nucleus tractus solitarii (NTS) pre-pro-glucagon (PPG) expression in chow-fed animals, it prevented the decrease in NTS PPG expression observed in HFD-fed control rats. Our findings demonstrate that intact VAN GLP-1R signaling is required for the full expression of the satiating, GE inhibiting and glycemia controlling effects of endogenous GLP-1 in chow-fed animals. In addition, VAN GLP-1R signaling appears to contribute to some of the hallmarks of HFD-induced obesity. Further studies are necessary to identify the exact mechanism(s) of the beneficial effects of GLP-1R KD with chronic HFD feeding. SNSF MHV grant PMPDP3_151360 (SJL), ETH Research Grant 47 12-2 (WL and SJL).