The cancer drug Dasatinib increases PGC-1α in adipose tissue but has adverse effects on glucose tolerance in obese mice

TY - JOUR

T1 - The cancer drug Dasatinib increases PGC-1α in adipose tissue but has adverse effects on glucose tolerance in obese mice

AU - Sylow, Lykke

AU - Long, Jonathan

AU - Lokurkar, Isha A

AU - Zeng, Xing

AU - Richter, Erik

AU - Spiegelman, Bruce M

N1 - CURIS 2016 NEXS 258

PY - 2016/11

Y1 - 2016/11

N2 - 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 andcauses glucose intolerance in obese mice. This should be considered in the treatment of chronic myeloid leukemia.

AB - 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 andcauses glucose intolerance in obese mice. This should be considered in the treatment of chronic myeloid leukemia.

U2 - 10.1210/en.2016-1398

DO - 10.1210/en.2016-1398

M3 - Journal article

C2 - 27589085

SN - 0013-7227

VL - 157

SP - 4184

EP - 4191

JO - Endocrinology

JF - Endocrinology

IS - 11

ER -