Fibroblast growth factor 21 (FGF21) functions as an endocrine hormone to regulate energy metabolism. Circulating FGF21 is derived from the liver and is produced in response to alterations of nutritional status. Here we show the effects of liraglutide, a human glucagon-like-peptide-1 (GLP-1) receptor agonist, injected into the third cerebral ventricle on body weight and plasma FGF21 levels in free-feeding mice, food-deprived mice, and mice provided 1 g after the injection. In free-feeding mice, liraglutide (5-100 mu g/kg) injected into the third cerebral ventricle suppressed food intake and body weight after 24h in a dose-dependent manner. Liraglutide (50 and 100 mu g/kg) significantly increased plasma FGF21 levels and hepatic FGF21 expression, whereas smaller doses (5 and 10 mu g/kg) had no effect. In food deprived mice, body weight did not differ significantly between the saline control and liraglutide-treated groups, but liraglutide (100 mu g/kg) significantly decreased plasma FGF21 levels at 24 h compared with the saline control. In mice provided 1 g food, body weight did not differ significantly between the saline control and liraglutide-treated groups, but liraglutide (50 mu g/kg) significantly decreased plasma FGF21 levels at 24 h compared with the saline control. These findings suggest that intracerebral injection of liraglutide decreases body weight by inhibiting food intake and increases plasma FGF21 levels in free-feeding mice, whereas it suppresses the elevations of plasma FGF21 levels induced by fasting or the restricted feeding. Thus, pharmacologic stimulation of central GLP-1 receptors has opposite effects on the alterations of plasma FGF21 levels induced by feeding and fasting. (C) 2015 Elsevier Ireland Ltd. All rights reserved.