The discovery of leptin in 19941 represented a tre-mendous breakthrough in the field of obesity and the regulation of energy balance. A system providing a circulating signal of satiety was hypothesized since the discovery of monogenic syndromes in mice with obesity and hyperphagia. 2 Classic parabiosis experiments suggested that ob/ob mice lack a hormone that limits food intake, while db/db mice have a defect in the cognate receptor, 3 and this hypothesis was later substantiated by the identification of leptin and its receptors. 1, 4 Leptin is the product of the obese (ob) gene and it is mainly expressed by the adipose tissue, although other sites also contribute to its expression. 5 Ob/ob mice express a truncated and inactive form of leptin, and the obesity is corrected by administration of the hormone. On the other hand, db/db mice express a signaling-incompetent leptin receptor, that makes these animals resistant to the actions of the hormone. 6 The leptin receptor (Ob-R) belongs to the class I cytokine receptor family and shares common features with the interleukin-6 receptor. 5 At last 6 isoforms of Ob-R are generated by alternative mRNA splicing, and Ob-Rb, also called the long isoform, is believed to be essential in mediating most of the biologic effects of leptin. Ob-Rb is expressed in the hypothalamus and in some peripheral tissues, and its activation triggers a signaling cascade involving the Jak family of protein tyrosine kinases and the Stat transcription factors. 5 The short isoforms, especially Ob-Ra, are abundantly expressed in most tissues, but the signaling capabilities of these receptors and their biologic significance are still debated.

Circulating leptin levels are related to the adipose tissue mass, and signal the central nervous system of the presence of sufficient energy stores, causing a response characterized by anorexia and increased energy expenditure. 7 However, the leptin pathway should not be regarded as simply an anti-obesity axis, because obese people have high circulating levels of leptin. 8 Accumulating evidence also indicates that leptin is a multifunctional cytokine, the actions of which extend well beyond those of the regulation of body weight. In fact, Ob-Rb is expressed in tissues such as the immune system, pancreatic islets, and placenta, and leptin has regulatory properties on many diverse processes such as the immune response, insulin secretion, angiogenesis, and wound