CONSTITUTIVE AND IMPAIRED SIGNALING OF LEPTIN RECEPTORS CONTAINING THE GLN-]PRO EXTRACELLULAR DOMAIN FATTY MUTATION

Leptin (OB), an adipocyte-secreted circulating hormone, and its recept or (OB-R) are key components of an endocrine loop that regulates mamma lian body weight, In this report we have analyzed signal transduction activities of OB-R containing the fatty mutation [OB-R(fa)], a single amino acid substitution at position 269 (Gln --> Pro) in the OB-R extr acellular domain that results in the obese phenotype of the fatty rat, We find that this mutant receptor exhibits both ligand-independent tr anscriptional activation via interleukin 6 and hematopoietin receptor response elements and ligand-independent activation of signal transduc er and activator of transcription (STAT) proteins 1 and 3, However, OB -R(fa) is unable to constitutively activate STAT5B and Is highly impai red for ligand induced activation of STATE compared with OB-R(wt). Int roduction of the fatty mutation into a OB-R/G-CSF-R chimera generates a receptor with constitutive character that is similar but distinct fr om that of OB-R(fa), Constitutive mutant OB-R(fa) receptor signaling i s repressed by coexpression of OB-R(wt), The implications of an extrac ellular domain amino acid substitution generating a cytokine receptor with a partially constitutive phenotype are discussed both in terms of the mechanism of OB-R triggering and the biology of the fatty rat.