Suppression of PDGF-induced PI3 kinase activity by imatinib promotes adipogenesis and adiponectin secretion

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 turn secrete high-molecular-weight adiponectin. Conversely, imatinib does not stimulate adiponectin secretion from mature adipocytes. We hypothesise that inhibition of PDGFRa (PDGFRA) and PDGFRb (PDGFRB) is the mechanism by which imatinib promotes adipogenesis. Supporting this, functional blocking antibodies to PDGFR promote adipogenesis and adiponectin secretion in MSC cultures. We have shown that imatinib is a potent inhibitor of PDGF-induced PI3 kinase activation and, using a PI3 kinase p110a-specific inhibitor (PIK-75), we have demonstrated that suppression of this pathway recapitulates the effects of imatinib on MSC differentiation. Furthermore, using mitogens that activate the PI3 kinase pathway, or MSCs expressing constitutively 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.

Platelet-Derived Growth Factor-BB Enhances Adipogenesis in Orbital Fibroblasts

“…32 Also proadipogenic effects of imatinib mesylate and dasatinib on multipotent mesenchymal stromal cells have been described. 33,34 In contrast to this, imatinib mesylate at a concentration of 2.5 lg/mL (the highest nontoxic concentration in our hands) blocked adipogenesis by orbital fibroblasts in our culture system (Supplementary Fig. S1), although not as efficient as dasatinib at that concentration.…”

c-Abl tyrosine kinase promotes adipocyte differentiation by targeting PPAR-gamma 2

“…These data imply that STI-571 positively regulates PPARγ and thus seemingly contradict the observations in our study. However, a recent study has found that these STI-571 effects on adipose and insulin homeostasis are attributed to its inhibition of PDFGR (40). We showed in this study that specific inhibition of c-Abl, either by RNA interference or by the timely administration of STI-571, has an antiadipogenic effect and interferes with PPARγ activity.…”

Adiponectin as a biomarker linking obesity and adiposopathy to hematologic malignancies

“…Adiponectin was capable of reversing imatinib resistance both in vitro (imatinib-resistant K562 CML cells) and in vivo [95]. Interestingly, imatinib improved glucose and lipid metabolism and increased adiponectin levels in CML patients by promoting adipogenesis via the suppression of PI3 kinase signaling downstream of plateletderived growth factor receptor (PDGFR) [96].…”