Effects of rosiglitazone treatment on the pentose phosphate pathway and glutathione-dependent enzymes in liver and kidney of rats fed a high-fat diet

Curr Ther Res Clin Exp. 2004 Jan;65(1):79-89. doi: 10.1016/S0011-393X(04)90007-0.


Background: Animals fed high-fat diets have been shown to develop hyperglycemia, insulin resistance, hyperlipidemia, and moderate obesity, which resemble the human metabolic syndrome. Obesity, the metabolic syndrome, and some thiazolidinediones, which act as insulin sensitizers, may increase oxidative stress, and/or influence the levels of cellular reducing equivalents and homeostasis.

Objective: This study investigated the effects of a high-fat diet, rosiglitazone, or a high-fat diet plus rosiglitazone on metabolic syndrome parameters and crucial liver and kidney enzyme activities in rats.

Methods: Male Wistar rats were assigned to 4 groups (n = 6 per group): (1) the fat (F) group was fed a rodent diet comprising 45 kcal% fat, (2) the rosiglitazone (R) group was fed a standard rat chow comprising 4.97 kcal% fat plus rosiglitazone (3 mg/kg.d), (3) the fat + rosiglitazone (FR) group was fed a rodent diet comprising 45 kcal% fat (as lard, product D12451) plus rosiglitazone (3 mg/kg.d), and (4) the control (C) group was fed a standard rat chow comprising 4.97 kcal% fat. Animals were housed for 4 weeks, at which time the liver and kidney were isolated for spectrophotometric determination of enzyme activities. Body weight was measured before treatment (baseline) and then weekly throughout the study. Adiposity was measured at the end of the 4 weeks.

Results: The activities of glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6-PGD), glutathione reductase (GR), and glutathione-S-transferase (GST) were significantly reduced in the livers of groups F, R, and FR compared with group C (all P < 0.05). Kidney G6PD, 6-PGD, and GR were found to be significantly lower in group R compared with the other groups (all P < 0.05). Kidney GST was similar in all groups. Plasma glucose, triglyceride, and insulin concentrations were significantly higher than in group F versus the other groups (all P < 0.05). Adiposity was increased in groups F and FR compared with groups C and R (all P < 0.05). Serum cholesterol concentrations were similar in all groups.

Conclusions: In this study, high-fat diet in rats decreased the enzyme activities responsible for pentose phosphate pathway and glutathione-dependent metabolism in liver but not in kidney. Similarly, these enzyme activities were inhibited with rosiglitazone treatment alone in both organs.

Keywords: glutathione-dependent metabolism; high-fat diet; metabolic syndrome; obesity; pentose phosphate pathway; rat; rosiglitazone.