BES2002 Oral Communications Metabolism (8 abstracts)
Regulation of leptin receptor cleavage
M Maamra 1 , M Bidlingmaier 2 , MC Postel-Vinay 3 , Z Wu 2 , CJ Strasburger 2 & RJM Ross 1
1Division of Clinical Sciences, Sheffield University, UK; 2Medizinische Klinik- Innenstadt, Muenchen, Germany; 3INSERM unite 344, Endocrinologie Moleculaire, Faculte de Medecine Necker, Paris, France.
The leptin receptor (ObR) exists in multiple isoforms. In humans, there is no mRNA encoding soluble receptor (LBP). We investigated the hypothesis that human LBP can be generated by proteolytic cleavage of membrane anchored leptin receptors (ObRb and ObRa). LBP, of similar size to that previously detected in human serum, was detected in medium of cells transfected with ObRa by HPLC, Immunofluorometric assay, and Ligand mediated immunofluorometric assay, but not by ELISA. The LBP in medium bound both leptin and an ObR specific antibody and the level of LBP correlated with receptor expression at the cell surface. There was increased accumulation of LBP, detected by LIFA and ELISA, after treatment with phorbol 12-myristate-13-acetate and N-ethylmaleimide (NEM), indicating that the production of LBP was up regulated by Protein Kinase C and sulfhydryl group activation. Dexamethasone in contrast had no effect on LBP levels. NEM also clearly induced a reduction in leptin binding by cell monolayers expressing membrane anchored ObR. The protease inhibitors, TAPI1 and Immunex Compound 2, could inhibit the production of LBP, indicating that the enzyme responsible for LBP cleavage belongs to the metalloprotease family.
Conclusion: human LBP is generated by proteolytic cleavage of membrane anchored leptin receptor by a metalloprotease. The levels of LBP are regulated by the availability of membrane anchored receptor, protein kinase C, and sulfhydryl group activation, but not by dexamethasone.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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