Immunogenetics

, Volume 65, Issue 1, pp 83–90

Influence of Tyrphostin AG490 on the expression of diabetes-associated markers in human adipocytes

Authors

    • Department of Pharmacotherapy and Translational Research, College of PharmacyUniversity of Florida
    • Department of Neurology, Miller School of MedicineUniversity of Miami
  • C. H. Wasserfall
    • Department of Pathology, Immunology and Laboratory MedicineUniversity of Florida
  • A. Hassanzadeh
    • Department of Pharmacotherapy and Translational Research, College of PharmacyUniversity of Florida
  • R. M. Cooper-DeHoff
    • Department of Pharmacotherapy and Translational Research, College of PharmacyUniversity of Florida
  • M. Wabitsch
    • Division of Pediatric Endocrinology, Diabetes and Obesity Unit, Department of Pediatrics and Adolescent MedicineUniversity of Ulm
  • M. Atkinson
    • Department of Pathology, Immunology and Laboratory MedicineUniversity of Florida
Brief Communication

DOI: 10.1007/s00251-012-0659-4

Cite this article as:
Davoodi-Semiromi, A., Wasserfall, C.H., Hassanzadeh, A. et al. Immunogenetics (2013) 65: 83. doi:10.1007/s00251-012-0659-4
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Abstract

Tyrosine kinase inhibitors (TKi) hold promise as a treatment for a variety of disorders ranging from those in oncology to diseases thought as immune mediated. Tyrphostin AG490 is a potent Jak-Stat TKi shown effective in the prevention of allograft transplant rejection, experimental autoimmune disease, as well as the treatment of cancer. However, given its ability to modulate this important but pleiotropic intracellular pathway, we thought that it is important to examine its effects on glucose metabolism and expression of major transcription factors and adipokines associated with insulin insensitivity and diabetes. We investigated the metabolic effects of AG490 on glucose levels in vivo using an animal model of diabetes, nonobese diabetic (NOD) mice, and transcription factor expression through assessment of human adipocytes. AG490 treatment of young nondiabetic NOD mice significantly reduced blood glucose levels (p = 0.002). In vitro, treatment of adipocytes with rosiglitazone, an insulin sensitizer that binds to peroxisome proliferator-activated receptor (PPAR) receptors and increases the adipocyte response to insulin, significantly increased the expression of the antidiabetic adipokine adiponectin. Importantly, the combination of rosiglitazone plus Tyrphostin AG490 further increased this effect and was specifically associated with significant upregulation of C-enhanced binding protein (C/EBP) (p < 0.0001). In terms of the mechanism underlying this action, regulatory regions of the PPARγ, ADIPOQ, and C/EBP contain the Stat5 DNA-binding sequences and were demonstrated, by gel shift experiments in vitro. These data suggest that blocking Jak-Stat signaling with AG490 reduces blood glucose levels and modulates the expression of transcription factors previously associated with diabetes, thereby supporting its potential as a therapy for this disease.

Keywords

AdipocytesDiabetesKinase inhibitorAutoimmunityAG490Obesity

Supplementary material

251_2012_659_MOESM1_ESM.docx (15 kb)
ESM 1(DOCX 14 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2012