Constitutive and impaired signaling of leptin receptors containing the Gln → Pro extracellular domain fatty mutation

David W. White, Yanping Wang, Streamson C. Chua, J. P. Morgenstern, Rudolph L. Leibel, Heinz Baumann, Louis A. Tartaglia

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Leptin (OB), an adipocyte-secreted circulating hormone, and its receptor (OB-R) are key components of an endocrine loop that regulates mammalian 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 extracellular domain that results in the obese phenotype of the fatty rat. We find that this mutant receptor exhibits both ligand-independent transcriptional activation via interleukin 6 and hematopoietin receptor response elements and ligand-independent activation of signal transducer and activator of transcription (STAT) proteins 1 and 3. However, OB-R(fa) is unable to constitutively activate STATSB and is highly impaired for ligand induced activation of STAT5B compared with OB-R(wt). Introduction of the fatty mutation into a OB-R/G- CSF-R chimera generates a receptor with constitutive character that is similar but distinct from that of OB-R(fa). Constitutive mutant OB-R(fa) receptor signaling is repressed by coexpression of OB-R(wt). The implications of an extracellular 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.

Original languageEnglish (US)
Pages (from-to)10657-10662
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number20
DOIs
StatePublished - Sep 30 1997

Keywords

  • Constitutive leptin receptor signaling
  • Obesity
  • Signal transducer and activator of transcription

ASJC Scopus subject areas

  • General

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