Feedback inhibition of leptin receptor/Jak2 signaling via Tyr 1138 of the leptin receptor and suppressor of cytokine signaling 3

Sarah L. Dunn, Marie Björnholm, Sarah H. Bates, Zhibin Chen, Matthew Seifert, Martin G. Myers

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

Leptin is an adipocyte-derived hormone that communicates the status of body energy stores to the brain to regulate feeding and energy balance. The inability of elevated leptin levels to adequately suppress feeding in obesity suggests attenuation of leptin action under these conditions; the activation of feedback circuits due to high leptin levels could contribute to this leptin resistance. Using cultured cells exogenously expressing the long form of the leptin receptor (LRb) or an erythropoietin receptor/LRb chimera, we show that chronic stimulation results in the attenuation of LRb signaling and the establishment of a state in which the receptor is refractory to reactivation. Mutation of LRb Tyr1138 (the site that recruits signal transducer and activator of transcription 3) alleviated this feedback inhibition, suggesting that signal transducer and activator of transcription 3 mediates the induction of a feedback inhibitor, such as suppressor of cytokine signaling 3 (SOCS3), during chronic LRb stimulation. Indeed, manipulation of the expression or activity of the LRb-binding tyrosine phosphatase, SH2-domaln containing phosphatase-2, by overexpression of wild-type and dominant negative isoforms or RNA interference-mediated knockdown did not alter the attenuation of LRb signals. In contrast, SOCS3 overexpression repressed LRb signaling, whereas RNA interference-mediated knockdown of SOCS3 resulted in increased LRb signaling that was not attenuated during chronic ligand stimulation. These data suggest that Tyr1138 of LRb and SOCS3 represent major effector pathways for the feedback inhibition of LRb signaling. Furthermore, we show that mice expressing an LRb isoform mutant for Tyr1138 display increased activity of the leptin-dependenf growth and immune axes, sugesting that Tyr 1138-mediated feedback inhibition may regulate leptin sensitivity in vivo.

Original languageEnglish (US)
Pages (from-to)925-938
Number of pages14
JournalMolecular Endocrinology
Volume19
Issue number4
DOIs
StatePublished - Apr 1 2005

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this