Abstract
Improved glucose and lipid metabolism is a unique side effect of imatinib therapy in some chronic myeloid leukaemia (CML) patients. We recently reported that plasma levels of adiponectin, an important regulator of insulin sensitivity, are elevated following imatinib therapy in CML patients, which could account for these improved metabolic outcomes. Adiponectin is secreted exclusively from adipocytes, suggesting that imatinib modulates adiponectin levels directly, by transcriptional upregulation of adiponectin in pre-existing adipocytes, and/or indirectly, by stimulating adipogenesis. In this report,we have demonstrated that imatinib promotes adipogenic differentiation of human mesenchymal stromal cells (MSCs), which in turnsecrete high-molecular-weight adiponectin. Conversely, imatinib does not stimulate adiponectin secretion from mature Adip ocytes. We hypothesise that inhibition of PDGFRα (PDGFRA) and PDGFRβ (PDGFRB) is the mechanism by whichimatinib promotes adipogenesis. Supporting this, functional blocking antibodies to PDGFR promote adipogenesis andadiponectin secretion in MSC cultures. We have shown that imatinib is a potent inhibitor of PDGF-induced I3 kinase activation and, using a PI3 kinase p110a-specific inhibitor (PIK-75), we have demonstrated that su p ression of this pathwazy recapitulates the effects of imatinib on MSC differentiation. Furthermore, using mitogens that activate the PI3 kinase pathway, or MSCs expressing constitutive ly activated Akt, we have shown that activation of the PI3 kinase pathway negates the pro-adipogenic effects of imatinib. Taken together, our results suggest that imatinib increases plasma adiponectin levels by promoting adipogenesis through the suppression of PI3 kinase signalling downstream of PDGFR.
Original language | English |
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Pages (from-to) | 229-240 |
Number of pages | 12 |
Journal | Journal of Molecular Endocrinology |
Volume | 48 |
Issue number | 3 |
DOIs | |
Publication status | Published or Issued - Jun 2012 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Biology
- Endocrinology