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Leptin plays important roles on the nutritional and energy status of the organism. It is secreted in an endocrine way by the
adipose tissue and in an exocrine way by the gastric mucosa. Gastric epithelial chief cells express and secrete leptin into the
gastric lumen through their RER-Golgi-secretory granules regulated pathway together with classical gastric enzymes such as
lipase and pepsinogen. Upon food intake, the content of the granules is released into the gastric lumen. Leptin resists the drastic
proteolytic conditions of the gastric juice thanks to its binding to the soluble isoform of the leptin receptor. The formation of the
leptin-leptin receptor complex takes place in the secretory granule prior release. Once secreted, this complex crosses the pyloric
sphincter reaching the duodenal lumen. Transmembrane leptin receptors lining the intestinal cells apical microvilli bind the
luminal leptin and internalize it through clathrin-coated vesicles. Leptin regulates absorption of nutrients and participates in
the intestinal mucosa integrity. However some of the internalized leptin is transported through transcytosis to the baso-lateral
membrane to be released into the interstitial space to reach the blood circulation and the hypothalamic target cells. Since leptin
is normally present in the gastric lumen and reaches the circulation through transcytosis across the intestinal cells, we designed
an oral formulation of leptin that by using the same pathway can reach the blood circulation. Such an oral formulation of leptin
is able to control food intake by various normal animal models and restores leptin levels in animal models expressing leptin
deficiency.
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