Obesity is increasing at an alarming rate in humans, while very little pharmacological handling seems to be successful in preventing abnormal regulation of energy intake that exceeds energy expenditure. Leptin is a key hormone that regulates energy homeostasis. First identified as secreted by the adipose tissue, it is also released by gastric epithelial cells. While adipose tissue leptin acts in the long-term for energy expenditure, gastric leptin is active on a short-term, being released at time of meals. Leptin is secreted in an exocrine fashion into the gastric lumen associated to its soluble receptor that protects it from the harsh conditions of the gastric and intestinal lumina. Once transported across the duodenal wall, leptin reaches circulation as the leptin-leptin receptor complex. The presence of leptin in the gastric cavity prompted us to put forward its oral administration. Oral leptin protected by anti-proteases reaches the gastric cavity and is channelled towards the duodenum. Upon crossing the intestinal epithelium, it reaches circulation in its leptin-leptin receptor form to get to hypothalamic and other target cells. Oral leptin induces major decreases in food intake and consequently in body weight in mice. Changes correlate with amounts of oral leptin and are even more drastic in ob/ob leptin-deficient obese mice. Oral leptin administration to young rats led to significant losses of body weight gain. Once given to dogs, the effect on food intake was significant demonstrating that oral leptin is efficient in small as well as large mammals. Beside its role in food intake, oral leptin targets the brown adipose tissue to stimulate lipid oxidation and lipolysis, leading to reduction of adiposity. Long-term administration of oral leptin does not alter gastric, duodenal or liver tissues. Oral administration of leptin appears as a promising avenue for the management of food intake and control of body weight.
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