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Endocrinology Vol. 142, No. 10 4389-4393
Copyright © 2001 by The Endocrine Society

ARTICLES

Generation of Human Soluble Leptin Receptor by Proteolytic Cleavage of Membrane-Anchored Receptors

M. Maamra, M. Bidlingmaier, M.-C. Postel-Vinay, Z. Wu, C. J. Strasburger and R. J. M. Ross

Division of Clinical Sciences (M.M., R.J.M.R.) Sheffield University, Sheffield S5 7AU, United Kingdom; Medizinische Klinik-Innenstadt (M.B., Z.W., C.J.S.), Muenchen 80336, Germany; and Institute National de la Santé et de la Recherche Médicale Unité 344 (M.-C.P.-V.), Endocrinologie Moleculaire, Faculte de Medecine Necker, Paris 75730 Cedex 15, France

Address all correspondence and requests for reprints to: Prof. R. J. M. Ross, Clinical Sciences, Northern General Hospital, Sheffield S5 7AU, United Kingdom. E-mail: r.j.ross{at}sheffield.ac.uk

The leptin receptor (ObR) exists in multiple isoforms. In rodents, a soluble isoform is generated by alternative splicing; but in humans, there is no mRNA encoding soluble receptor (leptin binding protein). We investigated the hypothesis that human leptin binding protein can be generated by proteolytic cleavage of membrane-anchored leptin receptors (ObRb and ObRa). Leptin binding protein of similar size to that previously detected in human serum was detected by HPLC in medium of cells transfected with ObRa. ObRa exhibited higher expression at the cell surface than ObRb and generated greater levels of leptin binding protein. Ligand-mediated immunofunctional and immunofluorometric assays revealed that the leptin binding protein in medium bound both leptin and an ObR-specific antibody and that the level of leptin binding protein correlated with receptor expression at the cell surface. Phorbol 12-myristate-13-acetate and N-ethylmaleimide increased the accumulation of leptin binding protein, an indication that the production of leptin binding protein was up-regulated by PKC and sulfhydryl group activation. The protease inhibitors, TNF{alpha} protease inhibitor 1 and Immunex compound 2, could inhibit the production of leptin binding protein, indicating that the enzyme responsible for leptin binding protein cleavage belongs to the metalloprotease family. In conclusion, human leptin binding protein is generated by proteolytic cleavage of membrane-anchored leptin receptor by a metalloprotease.




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