Endocrine Abstracts

Skeletal muscle and adipose tissue has been identified as an endocrine organ and their metabolism exerts an impact on whole-body metabolism. Endocrine functions attributed to adipokines and myokines are involved in body weight regulation and insulin sensitivity. Obesity is associated with dys-regulation of adipose tissue and skeletal muscle metabolism and is accompanied with insulin resistance. Our study investigates the effect of insulin regulated aminopeptidase (IRAP) inhibition on the regulatory mechanisms of metabolism of subcutaneous and visceral adipose tissue and skeletal muscle in the fully developed stage of obesity and insulin resistance in Zucker rats. The obese Zucker rats, the genetic model of obesity, pre-diabetes and metabolic syndrome, were administered with an IRAP inhibitor – HFI-419 (MerckMillipore, Germany) at a dose of 29 µg/100 g/day by osmotic minipumps. Glucose utilization was monitored by the intraperitoneal glucose tolerance test (ipGTT) and measured in the blood of the rat tail. In the tissues of interest, gene expression was determined by real-time quantitative PCR and protein expression was measured by Western blot. IRAP inhibition improved glucose utilization and significantly decreased the area under the curve for the glucose level during ipGTT. In visceral adipose tissue, we observed significantly up-regulated protein expression of Akt protein and AS160 (Akt substrate 160 kDa) protein phosphorylation in obese rats treated with HFI-419 in comparison with obese controls, indicating stimulation of the insulin receptorsignalling pathway. In subcutaneous fat depot, administration of HFI-419 significantly reduced expression of glucose transporter GLUT1. In skeletal muscle, significantly increased expression of sirtuin 1 (SIRT1) and superoxide dismutase1 and 2 (SOD1, SOD2), was found. Our results showed an improvement in glucose utilization during theglucose tolerance testafter administration of an IRAP inhibitor in insulin resistant obese Zucker rats. In the tissues studied, we revealed different molecular mechanisms leading to improvement of insulinsensitivity of these tissues. We conclude that thepositive metabolic effect of the IRAP inhibitor observed in obese rats is the improvement of glucose transport into adipocytes and theregulation of redox balance inskeletal muscle. The study was supported by grants VEGA 2/0174/17 and APVV-15-0229 grants.