ABSTRACT
T he hormone leptin plays an important role in the control o f body weight. Leptin is mainly produced and secreted by adipocytes as a 16 kDa nonglycosylated polypeptide and plasma leptin levels positively correlate with body fat energy stores. 1,2 To a lesser extent, leptin is also expressed in other tissues such as the epithelium o f the stomach, placenta, skeletal muscle and brain . 3,4 Spontaneous loss o f function mutations in the leptin encoding ob gene (for example in ob/ ob mice) give rise to a complex syndrome that includes morbid obesity, hypothermia, infertility, hyperglycemia, decreased insulin sensitivity and hyperlipidemia. 5 Leptin turned out to be a quite pleiotropic cytokine and its effects are not restricted to energy homeostasis, but also include neu roendocrine function ,6 angiogenesis,7 bone formation , 8 reproduction9 and immune responses. 10
Leptin mediates its effects by binding and activation o f the leptin receptor (LR), encoded by the db gene. 11 Loss o f function mutations in the db gene lead to a phenotype that is comparable to that o f the ob/ob mouse. The LR is a single-membrane spanning class I cytokine receptor. Like all members o f the class I cytokine receptor family, the receptor has no intrinsic kinase activity and uses cytoplasmic-associated Janus kinase 2 (JA K 2) for intracellular signalling. In a generally accepted model, leptin-binding leads to formation o f an activated receptor complex, allowing JA K 2 cross-phosphorylation. JA K 2 then rapidly phosphorylates several tyrosine residues in the cytosolic domain o f the receptor (in the case o f the mouse LR, tyrosines at positions 985,1077 and 1138). Phosphorylated tyrosines 1077 and 1138 bind STAT5 (signal transducer and activator o f transcription 5), while tyrosine 1138 further recruits STATI and STAT3 . 12,13 Although other STATs can be recruited, STAT3:STAT3 dimers are the most dominant after leptin stimulation. Once recruited, STATs themselves become a substrate for JA K s and homo-or heterodimerize upon phosphorylation, translocate to the nucleus and modulate transcription o f target genes. Other signalling pathways activated by the L R include M A PK 14 and phosphoinositide 3 kinase pathways. 15
Thus far, six LR isoforms have been identified (LRa-f ): one long form (LRb or LRlo) and four short forms (LRa,c,d,f ) are generated by alternative splicing. A sixth, soluble form (LRe) is a result o f ectodomain shedding and/or alternative splicing in respectively men and mice. High expres sion o f LRlo, the major signalling isoform, is observed in certain nuclei o f the hypothalamus, 16 a region o f the brain involved in the regulation o f body weight. Expression could also be shown in several other cell types including liver, pancreas, lung, kidney, adipose tissues, endothelial cells and cells o f the immune system, thereby forming the basis o f several peripheral biological func tions o f leptin.
