Abstract
We have recently demonstrated that signal transducers and activators of transcription (STATs) 1, 3, 5A, 5B, and 6 are expressed in both cultured and native adipocytes. Our current studies have focused on the activation of STATs 1 and 3 by leukemia inhibitory factor (LIF), oncostatin-M (OSM), and interferon-gamma (IFNgamma) in 3T3-L1 adipocytes. IFNgamma is shown to be a potent activator of STAT 1 as indicated by both tyrosine phosphorylation and nuclear translocation. However, LIF and OSM, which are potent inducers of STAT 3, are less potent activators of STAT 1 as measured by both tyrosine phosphorylation and nuclear translocation. Both STATs 1 and 3 were translocated to the nucleus in a time-dependent fashion following LIF treatment. In addition, IFNgamma resulted in a time- and dose-dependent effect on STATs 1 and 3 nuclear translocation. Growth hormone, a potent activator of STATs 5A and 5B, had a minimal effect on STAT 1 and STAT 3 tyrosine phosphorylation. Preincubation with either insulin or growth hormone had no detectable effects on the tyrosine phosphorylation or nuclear translocation of STATs 1 and 3 induced by LIF, OSM, or IFNgamma. The effects of LIF and IFNgamma on STAT 1 and 3 tyrosine phosphorylation and nuclear translocation were confirmed in native rat adipocytes. In 3T3-L1 adipocytes, a low level of serine phosphorylation of STAT 3 on residue 727 was observed and was markedly enhanced by insulin, LIF, or OSM. This increase in STAT 3 Ser727 phosphorylation was dependent upon the activation of MAPK, since the MAPK kinase inhibitor (PD98059) reduced STAT 3 Ser727 phosphorylation to basal levels. The inhibition of MAPK had no effect on the ability of STATs 1 and 3 to be tyrosine-phosphorylated or translocate to the nucleus. These studies demonstrate the highly specific and quantitative activation of STATs 1 and 3 by LIF, OSM, and IFNgamma in adipocytes and indicate that STAT 3 is a substrate for MAPK in adipocytes.
Highlights
Many recent studies suggest that the activation of particular signal transducer and activator of transcription (STAT) proteins may vary depending upon the cell type [1]
Cytosolic, and nuclear extracts were analyzed from 3T3-L1 adipocytes that were treated for 15 min with IFN␥, leukemia inhibitory factor (LIF), PDGF, Epidermal growth factor (EGF), growth hormone (GH), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, IL-4, or insulinlike growth factor I
Of the different STAT activators we examined, IFN␥, LIF, and OSM were potent activators of tyrosine phosphorylation and nuclear translocation of both STATs 1 and 3
Summary
Many recent studies suggest that the activation of particular STAT proteins may vary depending upon the cell type [1]. We have identified LIF, OSM, and IFN␥ as inducers of STAT 1 and 3 tyrosine phosphorylation and nuclear translocation in 3T3-L1 adipocytes. Pretreatment of adipocytes with either growth hormone or insulin had no effect on the ability of LIF, OSM, and IFN␥ to result in STAT 1 and 3 tyrosine phosphorylation or nuclear translocation.
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