Insulin signaling and Tau protein phosphorylation in the hippocampi of young and old obese Zucker fa/fa rats and their lean controls were assessed to determine whether obesity-induced peripheral insulin resistance and aging are risk factors for central insulin resistance and whether central insulin resistance is related to the pathologic phosphorylation of the Tau protein. Aging and obesity significantly attenuated the phosphorylation of the insulin cascade kinases Akt (protein kinase B, PKB) and GSK-3β (glycogen synthase kinase 3β) in the hippocampi of the fa/fa rats. Furthermore, the hyperphosphorylation of Tau Ser396 alone and both Tau Ser396 and Thr231 was significantly augmented by aging and obesity, respectively, in the hippocampi of these rats. Both age-induced and obesity-induced peripheral insulin resistance are associated with central insulin resistance that is linked to hyperTau phosphorylation. Peripheral hyperinsulinemia, rather than hyperglycemia, appears to promote central insulin resistance and the Tau pathology in fa/fa rats.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects host cells through angiotensin-converting enzyme 2 (ACE2). Concurrently, the product of ACE2 action, angiotensin 1–7 (Ang 1–7), binds to Mas receptors within the cardiovascular system and provides protective effects. Therefore, it is crucial to reveal the role of ACE2 inhibition, especially within pre-existing cardiovascular pathologies. In our study, we imitated the action of SARS-CoV-2 in organisms using the low dose of the ACE2 inhibitor MLN-4760 with the aim of investigating to what degree ACE2 inhibition is detrimental to the cardiovascular system of spontaneously hypertensive rats (SHRs), which represent a model of human essential hypertension. Our study revealed the complex action of MLN-4760 in SHRs. On the one hand, we found that MLN-4760 had (1) (pro)obesogenic effects that negatively correlated with alternative renin-angiotensin system activity and Ang 1–7 in plasma, (2) negative effects on ACE1 inhibitor (captopril) action, (3) detrimental effects on the small arteries function and (4) anti-angiogenic effect in the model of chick chorioallantoic membrane. On the other hand, MLN-4760 induced compensatory mechanisms involving strengthened Mas receptor-, nitric oxide- and hydrogen sulfide-mediated signal transduction in the aorta, which was associated with unchanged blood pressure, suggesting beneficial action of MLN-4760 when administered at a low dose.

Aerobic training lasting for 10 weeks elevates the adipose tissue FABP4, Giα, and adiponectin expression associated by a reduced protein oxidation

Angiotensin 1-7 (Ang 1-7) enhances insulin signaling and glucose transport activity in the skeletal muscle. The aim of our study was to evaluate the effect of AVE0991, a nonpeptide Mas receptor agonist, on the metabolic parameters, expression of RAS components and markers of oxidative stress, and insulin signaling in the skeletal morbidly obese rats. 33-week-old male obese Zucker rats were treated with vehicle and AVE0991 (0.5 mg/kg BW/day) via osmotic minipumps for two weeks. Gene expressions were determined by qPCR and/or Western blot analysis in musculus quadriceps. The enzymatic activities were detected flourometrically (aminopeptidase A) or by colorimetric assay kit (protein tyrosine phosphatase 1B). Administration of AVE0991 enhanced insulin signaling cascade in the skeletal muscle, reflected by improved whole-body glucose tolerance. It has been shown that reactive oxygen species (ROS) have insulin-mimetic action in muscle. The expression of renin receptor, transcription factor PLZF, and prooxidant genes was upregulated by AVE0991 accompanied by elevated expression of genes coding enzymes with antioxidant action. Our results show that AVE0991 administration activates genes involved in both ROS generation and clearance establishing a new prooxidant/antioxidant balance on a higher level, which might contribute to the improved insulin signaling pathway and glucose tolerance of obese Zucker rats.

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.