title: The Cancer Drug Dasatinib Increases PGC-1α in Adipose Tissue but Has Adverse Effects on Glucose Tolerance in Obese Mice.
abstract: Dasatinib (Sprycel) is a tyrosine kinase inhibitor approved for treatment of chronic myeloid leukemia. In this study, we identify dasatinib as a potent inducer of Peroxisome proliferator-activated receptor gamma coactivator (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 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 diet-induced obese and Ob/Ob mice. This correlated with increased hepatic PGC-1α expression and the gluconeogenesis genes phosphoenolpyruvate carboxykinase 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 chronic myeloid leukemia.
authors: Section of Molecular Physiology (L.S., E.A.R.), Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen 2100, Denmark; and Department of Cell Biology (J.L., I.A.L., X.Z., B.M.S.), Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
authors: Lykke
authors: L
authors: Sylow
authors: Section of Molecular Physiology (L.S., E.A.R.), Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen 2100, Denmark; and Department of Cell Biology (J.L., I.A.L., X.Z., B.M.S.), Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
authors: Jonathan Z
authors: JZ
authors: Long
authors: Section of Molecular Physiology (L.S., E.A.R.), Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen 2100, Denmark; and Department of Cell Biology (J.L., I.A.L., X.Z., B.M.S.), Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
authors: Isha A
authors: IA
authors: Lokurkar
authors: Section of Molecular Physiology (L.S., E.A.R.), Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen 2100, Denmark; and Department of Cell Biology (J.L., I.A.L., X.Z., B.M.S.), Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
authors: Xing
authors: X
authors: Zeng
authors: Section of Molecular Physiology (L.S., E.A.R.), Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen 2100, Denmark; and Department of Cell Biology (J.L., I.A.L., X.Z., B.M.S.), Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
authors: Erik A
authors: EA
authors: Richter
authors: Section of Molecular Physiology (L.S., E.A.R.), Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen 2100, Denmark; and Department of Cell Biology (J.L., I.A.L., X.Z., B.M.S.), Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
authors: Bruce M
authors: BM
authors: Spiegelman
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D000069439:Dasatinib / Q000009:adverse effects / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D015151:Immunoblotting; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D016133:Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D000069439:Dasatinib