We determined apolipoprotein AIV (apo AIV) content in intestinal epithelial cells using immunohistochemistry when leptin was administered intravenously. Most of the apo AIV immunoreactivity in the untreated intestine was located in the villous cells as opposed to the crypt cells. Regional distribution of apo AIV immunostaining revealed low apo AIV content in the duodenum and high content in the jejunum that gradually decreases caudally toward the ileum. Intraduodenal infusion of lipid (4 h) significantly increased apo AIV immunoreactivity in the jejunum and ileum. Simultaneous intravenous leptin infusion plus duodenal lipid infusion markedly suppressed apo AIV immunoreactivity. Duodenal lipid infusion increased plasma apo AIV significantly (measured by ELISA), whereas simultaneous leptin infusion attenuated the increase. These findings suggest that leptin may regulate circulating apo AIV by suppressing apo AIV synthesis in the small intestine.