The present study investigated the interaction of hypothalamic arcuate nucleus (ArcN) ghrelin and glucagon-like peptide-1 (GLP-1) signaling on metabolic function. Using indirect calorimetry, we first showed that acylated ghrelin, administered into the ArcN, significantly increased the respiratory exchange ratio (RER) in male Sprague–Dawley rats, representing a shift in fuel utilization toward enhanced carbohydrate oxidation and reduced lipid utilization. In contrast, treatment with similar doses of des-acyl ghrelin failed to induce reliable changes in RER. We then examined the ability of exendin-4 (Ex4) to alter acyl ghrelin’s energetic effects. Ex4 is a GLP-1 agonist and has been reported previously to suppress food intake in rodent models. Rats were treated with either systemic or direct ArcN Ex4, followed by acyl ghrelin. Our results indicated that both systemic and central injections of Ex4 alone significantly reduced RER and, importantly, Ex4 pretreatment reliably attenuated the impact of ghrelin on RER. Overall, these findings provide compelling evidence that ghrelin and GLP-1 signaling interact in the hypothalamic control of metabolic function.