Peripheral metabolic actions of leptin.

The ob gene product, leptin, is produced predominantly in adipose tissue. In ob/ob mice, a mutation in the ob gene prevents normal leptin production and results in a phenotype characterized by obesity and diabetes (Zhang et al. 1994). Daily injections of recombinant leptin to ob/ob mice inhibit food intake and reduce body weight and fat mass (Campfield et al. 1995; Halaas et al. 1995; Pelleymounter et al. 1995). This treatment also normalizes the blood glucose concentration and reduces the plasma insulin concentration of ob/ob mice (Pelleymounter et al. 1995). It was possible that the changes in glycaemia and insulin sensitivity in ob/ob mice given leptin might be a simple consequence of the antiobesity action. However, in pair-feeding studies, infusion of leptin not only resulted in a greater reduction in body fat than in the pair-fed mice, but the reduction in the plasma insulin concentration was much greater than that produced by an equivalent reduction in food intake (Levin et al. 1996). These findings suggested to us that leptin might have direct effects on a number of peripheral tissues associated with energy metabolism, including the endocrine pancreas and skeletal muscle. The leptin receptor (OB-R) is the product of the diabetes (db) gene (Chen et al. 1996; Lee et al. 1996) and was initially isolated as a complementary DNA (cDNA) from the choroid plexus cDNA library, encoding an 894 amino acid cell surface receptor which includes a hydrophobic signal sequence (Tartaglia et al. 1995). Structurally, OB-R is related to the class I cytokine receptor family, which includes gp 130, the common signal transducing chain for interleukin-6, leukaemia inhibitory factor receptor a-chain and the granulocyte colony-stimulatory factor. However, the interleukin-6, leukaemia inhibitory factor and granulocyte colony-stimulatory factor receptors all contain sequence motifs in the cytoplasmic domain that are required for interaction with janus kinase (JAK) and signal transduction and activation of transcription (STAT), whilst the OB-R from the choroid plexus lacks such a sequence. Further investigation showed that there are multiple isoforms of the OB-R, and a long form of the receptor (OB-Rb) was identified in the hypothalamus. It contained a long cytoplasmic domain of 302 amino acids, including consensus docking sites for JAK and STAT (Chen et al. 1996; Lee etal. 1996). The different isoforms of OB-Ra and OB-Rb are generated by alternative splicing, and additional short carboxyl terminal splice variants (OB-Rc, OB-Rd) and a soluble isoform lacking a transmembrane domain (OB-Re) have been identified also. The importance of the OB-Rb isofomi in the action of leptin was demonstrated by the finding of a point mutation (G + T transversion) in dh/db mice which results in a new splice donor site and, hence, a premature termination of translation (Chen et al. 1996; Lee et al. 1996). This truncated OB-R (db) isoform lacks the sequence motif required for JAK and STAT interaction and so db/db mice do not respond to leptin.