The generation of the soluble leptin receptor is dependent on TNF alpha Converting Enzyme (TACE)

The soluble leptin receptor (sOB-R) can modulate the bioavailability of leptin and thus effect the leptin/leptin receptor system in a regulatory manner. The genesis of sOB-R in vivo is differently realized in men and rodents: Whereas in the latter a specific alternatively spliced transcript exists, this could not be found in men. Hence a proteolytic dissociation from the membrane-bound leptin receptor is favoured in this case. The exact type of the protease is not known and neither is the OB-R isoform serving as substrate. One candidate for the enzyme is TACE/ADAM17 (tumor necrosis factor alpha converting enzyme). In order to assess the involvement of TACE in sOB-R shedding, we performed co-transfection experiments with leptin receptor and TACE cDNAs in HEK-293 cells. A significant higher amount of sOB-R was measured in the supernatants of cells co-transfected with mTACE cDNA in a dose-dependent manner as compared with cells transfected with OB-R only. Both the full length OB-R isoform (OB-Rb) and a shorter form (the extracellular domain coupled to a GPI-anchor) were used in the transfections, but solely with the shorter form a substantial shedding of sOB-R was measurable in our assay. This gives rise to the assumption that the shorter forms of the leptin receptor might serve as the major sources for sOB-R instead of the long form. Furthermore, a dependence on glucose concentration in the medium was observed: In experiments with “high glucose“ (25 mM) medium, the shedding was diminished by a factor up to 5.3 as compared with “normal glucose“ (17.5 mM) medium. Summarizing, we provide evidence that TACE is at least one important mediator for the generation of sOB-R which presumably derives from the shorter isoforms of the leptin receptor and is dependent on the glucose concentration in the extracellular environment.