The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms.
The action of leptin via the long form of its receptor (LepRb) is central to the control of body energy homeostasis and neuroendocrine function, but the mechanisms by which LepRb regulates intracellular signaling have remained incompletely understood. Here we demonstrate that leptin stimulates the phosphorylation of STAT5 and ribosomal protein S6 in the hypothalamic arcuate nucleus in mice. In cultured cells, we investigate the mechanisms by which leptin regulates each of these pathways. Our analysis reveals a dominant role for LepRb Tyr(1077) (which we demonstrate to be phosphorylated during receptor activation) and a secondary role for LepRb Tyr(1138) in the acute phosphorylation of STAT5a and STAT5b. Tyr(1138) and STAT3 attenuate STAT5-dependent transcription over the long-term, however. In contrast, Tyr(985) (the LepRb phosphorylation site required for ERK activation) mediates the phosphorylation of the ribosomal S6 kinase (RSK) and S6, as well as cap-dependent translation. Thus, these data demonstrate the phosphorylation of Tyr(1077) on LepRb during receptor activation, substantiate the hypothalamic regulation of STAT5 and S6 by leptin, and define the alternate LepRb signaling pathways that mediate each of these signals and their effects in cultured cells. Dissecting the contributions of these individual pathways to leptin action will be important for our ultimate understanding of the processes that regulate energy balance in vivo.
Gong
Yusong
Y
Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Ishida-Takahashi
Ryoko
R
Villanueva
Eneida C
EC
Fingar
Diane C
DC
Münzberg
Heike
H
Myers
Martin G
MG
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D004734:Energy Metabolism / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020738:Leptin / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000235:genetics / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
C515448:LEPR protein, human; D020738:Leptin; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012315:RNA Caps; D054411:Receptors, Leptin; D038601:Ribosomal Protein S6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; C515447:leptin receptor, mouse; C448579:ribosomal protein S6, mouse; D019893:Ribosomal Protein S6 Kinases; D048049:Extracellular Signal-Regulated MAP Kinases