The cancer drug Dasatinib increases PGC-1α in adipose tissue but has adverse effects on glucose tolerance in obese mice
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Dasatinib (Sprycel) is a tyrosine kinase inhibitor approved for treatment of chronic myeloid leukemia (CML). In this study we identify dasatinib as a potent inducer of PGC-1α mRNA. Dasatinib increased PGC-1α mRNA expression up to 6-fold in 3T3-F442A adipocytes, primary adipocytes, and epididymal white adipose tissue from lean and diet-induced obese (DIO) mice. Importantly, gene expression translated into increased PGC-1α protein content analyzed in melanoma cells and isolated mitochondria from adipocytes. However, dasatinib treatment had adverse effect on glucose tolerance in DIO and Ob/Ob mice. This correlated with increased hepatic PGC-1α expression and the gluconeogenesis genes PEPCK and glucose-6-phosphatase. In conclusion, we show that dasatinib is a potent inducer of PGC-1α mRNA and protein in adipose tissue. However, despite beneficial effects of increased PGC-1α content in adipose tissue, dasatinib significantly impaired glucose tolerance in obese, but not lean mice. As far as we are aware, this is the first study to show that dasatinib regulates PGC-1α and causes glucose intolerance in obese mice. This should be considered in the treatment of CML.
|Status||Udgivet - 2016|
CURIS 2016 NEXS 258