Abstract
OBJECTIVE: To investigate the effect of transcription-modulating drugs, fenofibrate and isotretinoin, on metabolic profile, insulin sensitivity of adipose and muscle tissues and gene expression in a genetic model of insulin resistance syndrome, polydactylous rat strain (PD/Cub).
DESIGN: Administration of fenofibrate (100 mg/kg/day), isotretinoin (30 mg/kg/day) or vehicle to adult male PD/Cub rats fed standard laboratory chow for 15 days.
MEASUREMENTS: Parameters of lipid and carbohydrate metabolism—oral glucose tolerance test, serum concentrations of insulin, triglycerides (TG), free fatty acids (FFA), glycerol, total cholesterol (CH); morphometric variables, in vitro insulin sensitivity of adipose and muscle tissues, catecholamine-stimulated lipolysis and the expression of ApoC-III and Hnf-4 genes in liver.
RESULTS: Both experimental groups displayed an increase in adiposity with contrasting effects on TG (lowered by fenofibrate and increased by isotretinoin) and gene expression (no change in fibrate-treated rats and increased expression of ApoC-III and Hnf-4 in isotretinoin-treated group). Fenofibrate-treated rats also showed decreased concentrations of FFA and CH with concomitant decrease of catecholamine-induced lipolysis in adipocytes, but also hyperinsulinemia and the highest insulin/glucose ratio. Isotretinoin increased glycerol concentrations and decreased the insulin sensitivity of peripheral tissues.
CONCLUSION: The PD/Cub rat showed a distinct pharmacogenetic reaction to fenofibrate and isotretinoin administration. Several lines of evidence now implicate specific variant(s) of ApoC-III and/or ApoA-V alleles as responsible for the dyslipidemia observed in this genetic model. The PD/Cub strain may also serve as a pharmacogenetic model for dissection of the retinoid-induced hypertriglyceridemia.
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Acknowledgements
This work was supported by following grants: No. 301/04/0248, No. 204/98/K015 from the Grant Agency of the Czech Republic and 6678-3 from the Internal Grant Agency of the Ministry of Health of Czech Republic.
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Sedova, L., Seda, O., Krenova, D. et al. Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome. Int J Obes 28, 719–725 (2004). https://doi.org/10.1038/sj.ijo.0802613
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DOI: https://doi.org/10.1038/sj.ijo.0802613
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