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. 2016 Nov;157(11):4184-4191.
doi: 10.1210/en.2016-1398. Epub 2016 Sep 2.

The Cancer Drug Dasatinib Increases PGC-1α in Adipose Tissue but Has Adverse Effects on Glucose Tolerance in Obese Mice

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The Cancer Drug Dasatinib Increases PGC-1α in Adipose Tissue but Has Adverse Effects on Glucose Tolerance in Obese Mice

Lykke Sylow et al. Endocrinology. .
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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.

Figures

Figure 1.
Figure 1.
A, qPCR-based screen in 3T3-F442A adipocytes for inducers of PGC-1α gene expression. Bar graph shows mRNA expression of PGC-1α in response to dasatinib, imatinib, or DMSO as vehicle control (10μM, 24-h incubation). B, Dose-response experiment of PGC-1α gene expression in response to dasatinib (24-h incubations) (20). DMSO, n = 9; 0.1μM, n = 2; 1μM, n = 3; 10μM, n = 7. C, Comparison of the effect of imatinib and dasatinib on PGC-1α gene expression in 3T3-F442A adipocytes (10-h incubation). DMSO, n = 9; dasatinib, n = 7; imatinib, n = 3. D, Western blotting showing PGC-1α protein in a dose-response experiment in PGC-1α-overexpressing melanoma cells stimulated with indicated concentration of dasatinib (6 h). E, PGC-1α protein expression during a time course experiment in PGC-1α-overexpressing melanoma cells stimulated with dasatinib for the indicated duration of time; n = 3–9, representing at least 3 independent experiments. Significant effect of treatment compared with DMSO vehicle control is indicated by **, P < .01. Values are mean ± SEM.
Figure 2.
Figure 2.
A, Bar graph showing the effect of imatinib and dasatinib on PGC-1α gene expression in primary adipocytes (from inguinal WAT) (10μM, 24-h incubation); n = 3–4. B, Bar graph showing the effect of imatinib and dasatinib on UCP-1 gene expression in primary adipocytes; n = 3–4. C, Nuclear fractionation experiment in primary adipocytes. Western blotting showing nuclear PGC-1α and TBP (control) protein in a dose-response experiment in primary adipocytes stimulated with the indicated concentrations of dasatinib. D, Protocol for ip injections and tissue collection. Bar graph showing the effect of ip injections of imatinib and dasatinib on PGC-1α gene expression in WAT (epididymal) in mice (50-mg/kg body weight); n = 5. E, Western blotting showing PGC-1α protein expression in nuclear fractionation of inguinal adipose tissue after ip injections of imatinib or dasatinib in WAT (epididymal) in mice (50-mg/kg body weight), or 4 hours of cold exposure (4°C). F, Bar graph showing the effect of ip injections of imatinib and dasatinib PGC-1α-1 (F), PGC-1α-4 (G), and PGC-1α-3 (H) gene expression in WAT (epididymal) in mice (50-mg/kg body weight); n = 5. I, Body weight in mice treated daily with 5- or 25-mg dasatinib per kg body weight for 7 days; n = 5. J, PGC-1α gene expression in mouse epididymal adipose tissue after 7 days of treatment of the indicated doses of dasatinib; n = 5. Significant effect of treatment compared with DMSO vehicle control is indicated by *, P < .05; **, P < .01; ***, P < .001. Values are mean ± SEM.
Figure 3.
Figure 3.
A, Body weight of DIO mice after 7 days of daily ip dasatinib administration; n = 11. B, Blood glucose concentration during a GTT in DIO mice; n = 11. PGC-1α (C) and UCP-1 (D) mRNA expression in eWAT, PGC-1α mRNA expression in muscle (E) and liver (F) tissue of DIO mice. Mitochondrial (G) and cytosolic (G) PEPCK, and G6Pase mRNA expression in liver from DIO mice; n = 11. H, Body weight of Ob/Ob mice after 7 days of daily ip dasatinib administration; n = 9–10. I, Blood glucose concentration during a GTT in Ob/Ob mice; n = 9–10. J, Blood glucose concentration during a GTT in lean mice and body weight in insert; n = 9–10. Significant effect of treatment compared with DMSO vehicle control is indicated by *, P < .05; ***, P < .001. Values are mean ± SEM.

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