LEPTIN-MEDIATED GENE-INDUCTION

摘要

Using the PC12 cell line as a model system a series of transcripts induced through activation of the leptin receptor or gp130 was identified. Based on kinetic studies on undifferentiated PC12 cells, two distinct gene-sets could be discerned: STAT-3, SOCS-3, Metallothionein-II, the serine/threonine kinase Fnk and the rat homologue of MRF-1 which are immediate early response genes, and Pancreatitis Associated Protein I, Squalene Epoxidase, Uridinediphosphate Glucuronyl Transferase and Annexin VIII, which are late induced target genes. In the latter case only, a strong co-stimulation with the adenylate cyclase activator forskolin was observed. Two additional transcripts encoding Leptin Induced Protein I (LIP-I) and Leptin Induced Protein II (LIP-II) were also identified. LIP-II is a rat orthologue of the human Down Syndrome Cell Adhesion Molecule (DS-CAM). In both cases, no forskolin co-stimulatory effect was observed. On PC12 cells differentiated to a neural phenotype by combined beta -NGF and forskolin treatment, Pancreatitis Associated Protein III, Peripherin and Mx2 protein were further identified as being regulated by leptin. Finally, from an RDA experiment using mRNA from either hyper-IL-6- or leptin-induced PC12 cells, the Reg gene, another member of the Pancreatitis Associated Protein family, and HIP-1 were identified as selectively up-regulated by H-IL-6. STAT-3 and SOCS-3 have been recognized in leptin signalling in vivo before. In this invention it is also demonstrated that leptin modulates the in vivo expression of the MT-II, Fnk and Pancreatitis Associated Protein I genes.