Glucagon-like peptide I (GLP-I) stimulates glucosedependent insulin secretion and inhibits food intake in the central nervous system. Because leptin reduces food intake but inhibits insulin secretion, we examined leptin action in mice with a null mutation in the GLP-I receptor. Intracerebroventricular leptin administration inhibited food intake in both wild-type and GLP-I receptor (GLP-IR) −/− mice, and daily intraperitoneal administration of leptin for 2 weeks produced comparable reductions in food intake and body weight in control and GLP-IR −/− mice. Glucose tolerance was improved in both wild-type and GLP-IR −/− mice, whether pair fed or leptin treated; however, blood sugars were significantly lower in the leptin-treated GLPIR −/− mice following oral glucose challenge (P < 0.01). Glucose-stimulated insulin was reduced in both pair-fed and leptin-treated mice (P < 0.01–0.001); however, insulin levels were significantly lower in leptin-treated versus pairfed GLP-IR −/− mice (P < 0.01). A single leptin injection had no effect on glucose tolerance in GLPIR −/− mice, but decreased hepatic PEPCK mRNA in both wild-type and GLP-IR −/− mice. The improvement in blood glucose excursion, despite lower levels of glucose-stimulated insulin in lean leptin-treated GLP-IR −/− mice, suggests that leptin may have beneficial effects on control of blood glucose in the absence of obesity. Furthermore, the greater effects of leptin on glucose and insulin in leptin-treated versus pair-fed GLP-IR −/− mice raises the possibility that disruption of GLP-I signaling modifies the sensitivity to leptin in vivo.