ABSTRACT
With the identification of leptin and its receptor, the physiological circuits controlling energy homeostasis have become increasingly well understood. In 1994, Friedman and colleagues showed that the severely obese Lepob/Lepob mice harbored mutations in the lep gene resulting in a complete lack of its protein product leptin (1). Administration of recombinant leptin reduced the food intake and body weight of leptin-deficient Lepob/Lepob mice and corrected all their neuroendocrine and metabolic abnormalities. Leptin acts through the long isoform of the leptin receptor (LEPRb), a member of the interleukin-6 receptor family of class 1 cytokine receptors. Leptin receptor has intracellular motifs necessary for activation of the Jak-STAT signal transduction pathway and leptin receptor activation ultimately results in phosphorylation of STAT3 which translocates into the nucleus to activate downstream target genes. The signaling form of the leptin receptor is deleted in leprdb/leprdb mice, which are consequently unresponsive to endogenous or exogenous leptin (2).
