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

Stephen Fitter1, Kate Vandyke, Stan Gronthos

  • 1Myeloma 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.

Journal of Molecular Endocrinology
|April 5, 2012
PubMed

Insights

Imatinib therapy enhances adiponectin levels by promoting adipogenesis in mesenchymal stromal cells (MSCs). This occurs through the suppression of PI3 kinase signaling, a key pathway regulated by PDGF receptors, leading to improved glucose and lipid metabolism in CML patients.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Imatinib therapy for chronic myeloid leukaemia (CML) is associated with improved glucose and lipid metabolism.
  • Elevated plasma adiponectin levels, a regulator of insulin sensitivity, have been observed post-imatinib treatment.
  • Adiponectin secretion from adipocytes suggests imatinib may influence adiponectin levels via adipogenesis or direct transcriptional effects.

Purpose of the Study:

  • To investigate the mechanism by which imatinib therapy increases plasma adiponectin levels.
  • To determine if imatinib promotes adipogenesis and adiponectin secretion in human mesenchymal stromal cells (MSCs).
  • To elucidate the signaling pathways involved in imatinib-induced adipogenesis, focusing on PDGF receptor and PI3 kinase signaling.

Main Methods:

  • Assessed imatinib's effect on adipogenic differentiation of human MSCs and adiponectin secretion.
  • Utilized functional blocking antibodies against PDGF receptors (PDGFRα and PDGFRβ) to study their role in adipogenesis.
  • Investigated imatinib's inhibition of PDGF-induced PI3 kinase activation and used a PI3 kinase inhibitor (PIK-75).
  • Examined the impact of activating the PI3 kinase pathway on imatinib's effects on MSC differentiation.

Main Results:

  • Imatinib promotes adipogenic differentiation of human MSCs, leading to increased secretion of high-molecular-weight adiponectin.
  • Imatinib does not directly stimulate adiponectin secretion from mature adipocytes.
  • Inhibition of PDGFRα and PDGFRβ signaling by imatinib is crucial for promoting adipogenesis.
  • Imatinib inhibits PDGF-induced PI3 kinase activation, and suppressing this pathway mimics imatinib's pro-adipogenic effects.
  • Activation of the PI3 kinase pathway negates the pro-adipogenic effects of imatinib.

Conclusions:

  • Imatinib increases plasma adiponectin levels by promoting adipogenesis in MSCs.
  • The mechanism involves the suppression of PI3 kinase signaling downstream of PDGF receptors.
  • These findings provide insight into the metabolic side effects of imatinib therapy in CML patients.

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