Pharmacogenomics of metabolic effects of rosiglitazone.
BACKGROUND
Thiazolidinediones are increasingly used drugs for the treatment of Type 2 diabetes. The individual response to thiazolidinedione therapy, ranging from the variable degree of metabolic improvement to harmful side-effects, is empirical, yet the underlying mechanisms remain elusive. In order to assess the pharmacogenomic component of thiazolidinediones' metabolic action, we compared the effect of rosiglitazone in two genetically defined models of metabolic syndrome, polydactylous (PD) and BN.SHR4 inbred rat strains, with their insulin-sensitive, normolipidemic counterpart, the Brown Norway (BN) rat.


METHODS
5-month-old male rats were fed a high-fat diet for 4 weeks, and the experimental groups received rosiglitazone (0.4 mg/100 g body weight) during the last 2 weeks of high-fat diet feeding. We assessed metabolic and morphometric profiles, oxidative stress parameters and gene expression in white adipose tissue.


RESULTS
In many followed parameters, we observed genetic background-specific effects of rosiglitazone administration. The mass and the sensitivity of visceral adipose tissue to insulin-stimulated lipogenesis increased with rosiglitazone treatment only in PD, correlating with a PD-specific significant increase in expression of prostaglandin D2 synthase. The glucose tolerance was enhanced in all strains, although fasting plasma glucose was increased by rosiglitazone in BN and BN.SHR4. Among the markers of lipid peroxidation, we observed the rosiglitazone-driven increase of plasma-conjugated dienes only in BN.SHR4. The genes with genotype-specific expression change included ADAM metallopeptidase domain 7, aquaporin 9, carnitine palmitoyltransferase 1B, caveolin 1, catechol-O-methyl transferase, leptin and prostaglandin D2 synthase 2.


CONCLUSIONS
Rosiglitazone's effects on lipid deposition and insulin sensitivity of peripheral tissues are largely dependent on the genetic background it acts upon.
Seda
Ondrej
O
Centre Hospitalier de l'Université de Montréal, Centre de Recherche, Technôpole Angus, 2901 Rachel East, Office 314, Montréal, Québec H1W 4A4, Canada.
Sedová
Lucie
L
Oliyarnyk
Olena
O
Kazdová
Ludmila
L
Krenová
Drahomíra
D
Corbeil
Gilles
G
Hamet
Pavel
P
Tremblay
Johanne
J
Kren
Vladimír
V
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002791:Cholesterol, Dietary / Q000494:pharmacology; D004032:Diet; D004040:Dietary Carbohydrates / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000096:biosynthesis; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D011914:Rats, Inbred BN; D011919:Rats, Inbred Strains; D000077154:Rosiglitazone; D013395:Sucrose / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*
D002791:Cholesterol, Dietary; D004040:Dietary Carbohydrates; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D008055:Lipids; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D013395:Sucrose; D012313:RNA; D006003:Glycogen; D005947:Glucose