Abstract
The aim of our study was to determine the influence of inhibition of insulin-regulated aminopeptidase/oxytocinase (IRAP) on glucose tolerance and metabolism of skeletal muscle and visceral adipose tissue in obese Zucker rats. Obese Zucker rats administered with IRAP inhibitor–HFI-419 at a dose of 29 μg/100 g BW/day by osmotic minipumps implanted subcutaneously for 2 weeks. Two-hour intraperitoneal glucose tolerance test (ipGTT) was performed in fasting rats. Plasma oxytocin levels were measured by enzyme immunoassay after plasma extraction. In the musculus quadriceps and epididymal adipose tissue, the expression of factors affecting tissue oxidative status and metabolism was determined by real-time qPCR and/or Western blot analysys. The plasma and tissue enzymatic activities were determined by colorimetric or fluorometric method. Circulated oxytocin levels in obese animals strongly tended to increase after HFI-419 administration. This was accompanied by significantly improved glucose utilization during ipGTT and decreased area under the curve (AUC) for glucose. In skeletal muscle IRAP inhibitor treatment up-regulated enzymes of antioxidant defense system – superoxide dismutase 1 and 2 and improved insulin signal transduction pathway. HFI-419 increased skeletal muscle aminopeptidase A expression and activity and normalized its plasma levels in obese animals. In epididymal adipose tissue, gene expression of markers of inflammation and adipocyte hypertrophy was down-regulated in obese rats after HFI-419 treatment. Our results demonstrate that IRAP inhibition improves whole-body glucose tolerance in insulin-resistant Zucker fatty rats and that this metabolic effect of HFI-419 involves ameliorated redox balance in skeletal muscle.
Highlights
Obesity comprises one of the key risk factors for the metabolic syndrome and contributes to the development of insulin resistance and subsequently to type two diabetes mellitus, atherogenic dyslipidemia and cardiovascular disease (Ritchie and Connell, 2007)
The ANOVA with repeated measures revealed significant interaction between time and group of rats (p < 0.001) and subsequent post hoc analysis detected that HFI-419 treatment in obese rats led to decline of blood glucose at 30 (p < 0.001), 60 (p < 0.001), and 90 (p < 0.01) min after the glucose load when compared with obese animals treated with vehicle (Figure 1A)
In order to investigate the impact of Insulin-regulated aminopeptidase (IRAP) inhibition on peripheral glucose tolerance and skeletal muscle and adipose tissue metabolism, we treated obese Zucker rats with HFI-419, a specific inhibitor of IRAP catalytic activity, for 2 weeks
Summary
Obesity comprises one of the key risk factors for the metabolic syndrome and contributes to the development of insulin resistance and subsequently to type two diabetes mellitus, atherogenic dyslipidemia and cardiovascular disease (Ritchie and Connell, 2007). The Zucker fatty rat represents a well-established model of human obesity and insulin resistance. Obesity in this animal model is a consequence of spontaneous mutation (fa) in the gene encoding the leptin receptor resulting in hyperphagia (Phillips et al, 1996). IRAP has been proposed as the surrogate marker of insulin-regulated vesicular traffic along with GLUT4 since the presence of IRAP is required for maintaining normal insulin-dependent translocation as well as forming an insulinresponsive vesicular compartment at the plasma membrane (Gross et al, 2004)
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