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 of OB-R have been described: long form (OB-R(L)) characterized as a signal transducing receptor that is highly expressed in specific nuclei of the hypothalamus; and a short, signaling-defective form (OB-R(S)) of indeterminate function that is ubiquitously expressed throughout the body. Receptor chimera studies indicate that OB-R(L) signals via homo-oligomers. However, co-expression experiments have demonstrated that signaling by OB-R(L) is only marginally susceptible to dominant negative suppression by OB-R(S). In the present study we have used receptor epitope tagging to analyze the ligand-independent and -dependent association properties of OB-R(S) and OB-R(L). We present evidence for ligand-independent homo-oligomerization by both receptor isoforms. Ligand treatment of these complexes does not dramatically augment homo-oligomerization. In contrast, hetero-oligomerization between long and short OB-R cannot be detected in the absence of ligand but can be resolved in the 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).