Oral administration of leptin for the control of food intake and weight management
Leptin performs fundamental functions that regulate appetite and energy expenditure. Originally discovered as an adipokine, it is also secreted by major gastric cells in an exocrine regulated fashion. To overcome the harsh conditions of gastric juice, a chaperone, the soluble isoform of its receptor, forms. The released leptin-leptin receptor complex is channeled into the intestinal lumen. The leptin is then internalized by the duodenal enterocytes, transcited, and released into the circulation to reach the target cells.
The physiological presence of leptin in gastric juice led us to present the proposal for an oral administration of leptin. Oral leptin administered in an appropriate vehicle that protects from early degradation by gastric and pancreatic juices and promotes internalization by intestinal cells, led to its rapid appearance in circulation. Once administered to normal and obese mice, oral leptin decreased food intake by 60% and significantly reduced body weight.
The effects were proportional to the amounts administered. By adjusting them, we were able to reduce and stabilize body weight in ob / ob obese mice for long periods of time. Dog studies using an oral tablet containing leptin with the different components that protect and promote leptin internalization have shown its effectiveness in reducing food intake. Other studies showed that oral leptin stimulated brown adipose tissue. It activates UCP1 and other mitochondrial enzymes for lipid oxidation, lipolysis, and decreases fat synthesis, leading to rapid reduction in body weight and adiposity. Taken together, these results demonstrate that oral leptin reaches blood circulation and target cells very efficiently. In addition to acting as a satiety hormone that reduces appetite and decreases food intake, oral leptin triggers lipolysis for general body weight loss. By demonstrating that long-term oral administration of leptin to mice led to reduced food intake and control of body weight, we decided in the present study to evaluate the effect of short-term oral administration of leptin to dogs. . An optimal vehicle was designed to administer leptin orally to dogs. One dose consisted of various components and 1 mg of encapsulated leptin. The pill was easily swallowed by the dog. Animals were presented with food one hour later and food intake was measured. The experiments were carried out early in the morning or early in the afternoon. The results systematically demonstrated that after oral administration of leptin the animals reduced their food intake. The reduction in the amount of food eaten varied from 15% to 55%, depending mainly on the time of day. Oral leptin administration was more efficient in the morning than in the afternoon. The success of the treatment was related to the efficiency of leptin absorption. A high correlation was found between circulating levels of exogenous leptin and amounts of food intake. Based on these results and those previously obtained in rodents, we propose that oral administration of leptin represents an excellent approach to control food intake.
