Myeloma Research Laboratory, Bone and Cancer Research Laboratories, Department of Haematology, Institute of Medical and Veterinary Science, Centre for Cancer Biology, SA Pathology, GPO Box 14, Adelaide, South Australia 5000, Australia.
J Mol Endocrinol. 2012 May 8;48(3):229-40. doi: 10.1530/JME-12-0003. Print 2012 Jun.
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 PDGFRα (PDGFRA) and PDGFRβ (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 p110α-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.
改善葡萄糖和脂质代谢是伊马替尼治疗某些慢性髓性白血病（CML）患者的独特副作用。我们最近报道，CML 患者接受伊马替尼治疗后，血浆脂联素水平升高，脂联素是胰岛素敏感性的重要调节剂，这可能是这些代谢改善的原因。脂联素仅由脂肪细胞分泌，这表明伊马替尼通过转录上调预先存在的脂肪细胞中的脂联素，直接调节脂联素水平，和/或通过刺激脂肪生成间接调节脂联素水平。在本报告中，我们已经证明伊马替尼促进了人间充质基质细胞（MSCs）的成脂分化，进而分泌高分子量的脂联素。相反，伊马替尼不会刺激成熟脂肪细胞分泌脂联素。我们假设抑制 PDGFRα（PDGFRA）和 PDGFRβ（PDGFRB）是伊马替尼促进脂肪生成的机制。支持这一观点的是，针对 PDGFR 的功能性阻断抗体可促进 MSC 培养物中的脂肪生成和脂联素分泌。我们已经表明，伊马替尼是 PDGF 诱导的 PI3 激酶激活的有效抑制剂，并且使用 PI3 激酶 p110α 特异性抑制剂（PIK-75），我们已经证明抑制该途径可再现伊马替尼对 MSC 分化的影响。此外，使用激活 PI3 激酶途径的有丝分裂原，或表达组成型激活 Akt 的 MSCs，我们已经表明激活 PI3 激酶途径否定了伊马替尼的促脂肪生成作用。综上所述，我们的研究结果表明，伊马替尼通过抑制 PDGFR 下游的 PI3 激酶信号通路促进脂肪生成，从而增加血浆脂联素水平。
