Interactions between leptin and exendin-4, a glucagon-like peptide-1 agonist, in the regulation of food intake in the rat

Leptin interplays with other peptides to control feeding behaviour in humans and animals. Using exendin-4, an agonist of glucagon-like peptide-1, we investigated whether leptin modifies its effect on food intake in the rat. In the first series, exendin-4 alone (0.1, 2 or 10 mu g per rat), leptin alone (0.1, 2, 10 or 100 mu g per rat) or exendin-4 and leptin together (0.1 + 0.1, 2 + 2, 10 + 10, or 2 + 100 mu g per rat, respectively) were injected once intraperitoneally. In the second series animals were injected either with exendin-4 (2 mu g) alone, leptin (10 mu g) alone, or leptin (10 mu g) + exendin-4 (2 mu g) daily for 5 subsequent days. At the lowest dose used, leptin and exendin-4 injected once together, but not separately, reduced significantly a 24-hour food intake. When used in higher doses, however, leptin did not change the exendin-4-dependent suppressory effect on food consumption. No significant differences in food intake were seen between rats treated repeatedly with exendin-4 only and animals injected with both drugs. Hence, leptin and exendin-4 may act additively to inhibit appetite when present in low concentrations while, at high leptin doses, this effect is abolished. The lack of synergistic effects of exendin-4 and high leptin concentrations on food intake may explain, at least in part, mechanisms responsible for leptin resistance in subjects with hyperleptinaemia.