Leptin is a cytokine hormone with various roles throughout the body. Recent research has shown that circulating leptin is able to enter the digestive tract in a form that retains signalling potential1. As the fate of leptin in the digestive tract is essentially unknown, a 2 h time course experiment was designed to explore this. Random bred male Swiss mice (8 weeks of age) were lightly anaesthetised using ether before receiving 12 ng of 125I-lablelled leptin by intragastric gavage. Animals were returned to individual cages before euthanasia (n=4 per time). Tissues were collected to determine 125I-leptin distribution and TCA precipitation was performed to assess its intactness. Over the course of the experiment the amount of 125I-leptin recovered from the stomach contents declined to 23.5 ± 2.2 % of the administered dose, while within the small intestine contents a wave of approximately 3-8 % of the dose was detected moving distally. In the hindgut lumen 0.7 ± 0.4 % of the dose was recovered 30 min after administration, increasing to 3.9 ± 1.7 % of the dose 120 min after administration. Throughout the experiment 125I-leptin was recovered from the circulation with 3.1 ± 1.2 % to 4.1 ± 0.5 % of the total dose calculated in the entire blood volume and 73.0 ± 6.2 % intact. These data are the first to indicate that leptin is capable of entering the circulation from the digestive tract. When viewed in conjunction with the recent report of leptin entering the digestive tract from the circulation1, it would appear that leptin may cycle between the circulation and digestive tract. As in vitro experiments have shown that leptin regulates nutrient absorption2,3, there may be a major role for leptin in energy homeostasis by acting directly in the digestive tract.