title: Feedback inhibition of leptin receptor/Jak2 signaling via Tyr1138 of the leptin receptor and suppressor of cytokine signaling 3.
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-domain 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-dependent growth and immune axes, suggesting that Tyr1138-mediated feedback inhibition may regulate leptin sensitivity in vivo.
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0638, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Dunn
authors.forename: Marie
authors.initials: M
authors.lastname: Björnholm
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Bates
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Chen
authors.forename: Matthew
authors.initials: M
authors.lastname: Seifert
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D053614:Janus Kinase 2; D020738:Leptin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D017467:Receptors, Erythropoietin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D054411:Receptors, Leptin; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*
chemical_list: C515448:LEPR protein, human; D020738:Leptin; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D017467:Receptors, Erythropoietin; D054411:Receptors, Leptin; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; C515447:leptin receptor, mouse; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases