Evidence for ligand-independent homo-oligomerization of leptin receptor (OB-R) isoforms: A proposed mechanism permitting productive long-form signaling in the presence of excess short-form expression

The adipocyte secreted hormone leptin (OB) and its receptor (OB-R) are key regulators of mammalian body weight homeostasis. Two predominant isoforms o f OB-R have been described: long form (OB-R-L) characterized as a signal tr ansducing receptor that is highly expressed in specific nuclei of the hypot halamus; and a short, signaling-defective form (OB-R-S) of indeterminate fu nction that is ubiquitously expressed throughout the body. Receptor chimera studies indicate that OB-R-L signals via homo-oligomers. However, co-expre ssion experiments have demonstrated that signaling by OB-R-L is only margin ally susceptible to dominant negative suppression by OB-R-S. In the present study we have used receptor epitope tagging to analyze the ligand-independ ent and -dependent association properties of OB-R-S and OB-R-L. We present evidence for ligand-independent homo-oligomerization by both receptor isofo rms. Ligand treatment of these complexes does not dramatically augment homo -oligomerization. In contrast, hetero-oligomerization between long and shor t OB-R cannot be detected in the absence of ligand but can be resolved in t he presence of ligand. Deletion and substitution mutagenesis of the OB-R-L intracellular domain indicates that ligand-independent homo-oligomerization by OB-R-L is sensitive to reduction in JAK kinase recruitment capability, suggesting that JAK interaction and signaling competency may provide means for isoform specific OB-R sorting. these results are discussed with regard to possible mechanisms permitting efficient leptin-induced signaling by OB- R-L in tissues that co-express OB-R-S. (C) 1999 Wiley-Liss, Inc.