Peripheral metabolic actions of leptin

Abstract

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. Kieffer et al. ...

Fatty acid oxidation and triacylglycerol hydrolysis are enhanced after chronic leptin treatment in rats

“…Acutely, leptin reduces insulin secretion in isolated pancreatic islet cells (9,40). In this study, chronic leptin treatment reduced serum insulin.…”

Significant Increase in Maternal Plasma Leptin Concentration in Induced Delivery: A Possible Contribution of Pro-inflammatory Cytokines to Placental Leptin Secretion

“…One possibility may be that a gradual increase in leptin concentration and chronic hyperleptinemia may reduce the sensitivity of the satiety center to leptin, but that the center may respond to a further increase in leptin during labor. On the other hand, leptin promotes mobilization of energy from adipose tissue to peripheral organs, and stimulates energy utilization in these peripheral organs [33]. It also promotes utilization of glucose in peripheral organs including muscle [34].…”

Free-to-Total Leptin Ratio in Maternal Plasma is Constant Throughout Human Pregnancy

“…In fact, the appetite of pregnant women is not suppressed during pregnancy, suggesting the presence of resistance to the satiety effect of leptin. Another major activity of leptin is to increase insulin sensitivity in peripheral tissues such as muscle, liver, and adipose tissue, and thus leptin stim- ulates energy utilization in these peripheral tissues [20]. The rapidly growing fetus can be regarded as one of the peripheral tissues since it is solely dependent on the energy supply from the mother.…”