Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome.
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).


METHODS
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.


METHODS
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.


CONCLUSIONS
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.
Sedova
L
L
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Seda
O
O
Krenova
D
D
Kren
V
V
Kazdova
L
L
D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D011345:Fenofibrate / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D005951:Glucose Tolerance Test; D051557:Hepatocyte Nuclear Factor 4; D015228:Hypertriglyceridemia / Q000139:chemically induced; D000960:Hypolipidemic Agents / Q000633:toxicity*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D015474:Isotretinoin / Q000633:toxicity*; D008055:Lipids / Q000097:blood; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D000960:Hypolipidemic Agents; D007328:Insulin; D008055:Lipids; D010750:Phosphoproteins; D014157:Transcription Factors; D015474:Isotretinoin; D011345:Fenofibrate