Perspectives in the therapeutic use of leptin

The cloning and characterisation of the protein encoded by the ob gene, called leptin, has represented an enormous advance in the knowledge we have at the present time on the control of appetite and the regulation of body weight. Animal experiments have shown that this adipocyte-derived hormone informs the hypothalamus about the magnitude of fat stores and induces changes in eating behaviour and thermogenesis directed to maintain nutritional homeostasis. Besides the CNS and adipose tissue, other tissues like the gonads, adrenals, pancreas, blood vessels, immune cells and bone are also targets for leptin action, setting the basis for the pleiotropic character of leptin. In contrast to ob(-)/ob(-) mice, which have leptin deficiency, obese patients usually exhibit hyperleptinaemia due to leptin resistance of uncertain aetiology. Patients with congenital leptin deficiency show a dramatic response to recombinant leptin therapy in terms of body weight and fat reduction. However, in contrast to animals, no thermogenic effect has been demonstrated in humans treated with leptin. Leptin-resistant obese subjects display a heterogeneous response to leptin treatment, though some patients achieve a significant weight loss when receiving high doses. New formulations are being tried with different success rates. Before leptin can play a role in the treatment of obesity, more studies are needed to discover which is the adequate dose, which the best route and form of administration and how we can select the patients who will benefit from this particular therapy. The development of new leptin analogues with high penetrating capacity to cross the blood-brain barrier and the investigation of other approaches to overcome the leptin resistance are awaited. Future applications of leptin may be directed to the treatment of infertility, wound healing and bone remodelling among others.