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Metabolic syndrome is represented by a group of interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, and hypertension. The incidence of metabolic syndrome is rapidly increasing worldwide, becoming a major public and clinical problem. There has been an explosion of scientific research in regard of food-derived bioactive protein peptides. Our previous research has identified three egg white protein ovotransferrin-derived ACE-inhibitory peptides, IRW, IQW, and LKP. Among them, IRW showed anti-inflammatory and anti-oxidant ability in vitro and in vivo. Herein, we investigated the effect of EWH and egg white-derived peptide, IRW, on TNF-α-induced insulin resistance and its underlying molecular mechanism by testing glucose uptake, GLUT4 translocation, and insulin-signaling pathway using rat skeletal muscle cells (L6). To induce insulin resistance, we incubated L6 myotubes with TNF-α for 24 h. The role of EWH and IRW in preventing TNF-α-induced insulin resistance was studied by co-incubation of TNF-α in the presence of EWH or IRW.
Insulin resistance was induced by treating rat-derived L6 cells with 5 ng/ml TNF-α for 24 h. Effects of Egg white hydrolysate (EWH) and Egg White-Derived Antihypertensive Peptide (IRW) on glucose uptake were detected by glucose uptake assay, glucose transporter 4 (GLUT4) translocation by immunofluorescence, and western blot, while insulin-signaling pathway and mitogen-activated protein kinase (MAPK) pathway were investigated using western blot.
Adding both EWH and IRW significantly improved glucose uptake in TNF-α-treated cells, increased activation of insulin receptor substrate (IRS-1) tyrosine residue and protein kinase B (Akt), whereas decreased activation of IRS-1 serine residue. In addition, TNF-α-induced activation of p38-mitogen-activated protein kinase (p38) and c-Jun N-terminal kinases (JNK) 1/2 were decreased by either EWH or IRW treatment. EWH and IRW improve impaired insulin sensitivity by down-regulating the activation of p38 and JNK1/2 in TNF-α-treated skeletal muscle cells.
In conclusion, the present study shows, for the first time, that EWH processed by thermolysin and pepsin, and egg white-derived tripeptide, IRW, improves impaired insulin sensitivity by down-regulating the activation of p38 and JNK1/2 in TNF-α-treated skeletal muscle cells. Our results provide an important insight for further investigating of food protein hydrolysates and peptides as a novel therapeutic alternation against metabolic syndrome and help to illustrate their mechanism of action.