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Chapter category:

Insights in the Activated LR Complex and the Rational Design of Antagonists

Chapter authors:
Frank Peelman, Lennart Zabeau and Jan Tavernier

The hormone leptin plays an important role in the control of 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. To a lesser extent, leptin is also expressed in other tissues such as the epithelium of the stomach, placenta, skeletal muscle and brain. Spontaneous loss of 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. Leptin turned out to be a quite pleiotropic cytokine and its effects are not restricted to energy homeostasis, but also include neuroendocrine function, angiogenesis, bone formation, reproduction and immune responses. Leptin mediates its effects by binding and activation of the leptin receptor (LR), encoded by the db gene. Loss of function mutations in the db gene lead to a phenotype that is comparable to that of the ob/ob mouse. The LR is a single‑membrane spanning class I cytokine receptor. Like all members of the class I cytokine receptor family, the receptor has no intrinsic kinase activity and uses cytoplasmic‑associated Janus kinase 2 ( JAK2) for intracellular signalling. In a generally accepted model, leptin‑binding leads to formation of an activated receptor complex, allowing JAK2 cross‑phosphorylation. JAK2 then rapidly phosphorylates several tyrosine residues in the cytosolic domain of the receptor (in the case of the mouse LR, tyrosines at positions 985, 1077 and 1138). Phosphorylated tyrosines 1077 and 1138 bind STAT5 (signal transducer and activator of transcription 5), while tyrosine 1138 further recruits STAT1 and STAT3. Although other STATs can be recruited, STAT3:STAT3 dimers are the most dominant after leptin stimulation. Once recruited, STATs themselves become a substrate for JAKs and homo‑ or heterodimerize upon phosphorylation, translocate to the nucleus and modulate transcription of target genes. Other signalling pathways activated by the LR include MAPK14 and phosphoinositide 3 kinase pathways. 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 of ectodomain shedding and/or alternative splicing in respectively men and mice. High expression of LRlo, the major signalling isoform, is observed in certain nuclei of the hypothalamus, a region of the brain involved in the regulation of body weight. Expression could also be shown in several other cell types including liver, pancreas, lung, kidney, adipose tissues, endothelial cells and cells of the immune system, thereby forming the basis of several peripheral biological functions of leptin.

Frank Peelman

Lennart Zabeau

Jan Tavernier
Department of Medical Protein Research, VIB, and Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University

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