Abstract
Insulin resistance (IR) is the main pathogenesis of metabolic syndrome and a shared pathophysiological change in conditions such as diabetes mellitus, adiposity, hypertension, and atherosclerosis. Visceral adipose tissue-derived serpin (Vaspin) is a newly discovered adipocytokine with insulin-sensitizing and anti-inflammatory effects. To examine if vaspin can improve insulin resistance in rats fed a high-fat diet via the insulin receptor substrate/phosphatidylinositol 3 kinase/protein kinase B/glucose transport (IRS/PI3K/Akt/Glut) and inhibitory κB alpha/nuclear factor-kappa B (IκBα/NF-κB) signalling pathways, thirty male Sprague-Dawley (SD) rats were randomly divided into three groups: the normal control group (NC group, n = 10), high-fat diet group (HFD group, n = 10) and vaspin intervention group (HFD + vaspin group, n = 10). Results showed that intervention with vaspin significantly decreased fasting blood glucose (FBG) and fasting insulin (FINS) concentrations in HFD − fed rats without significantly affecting body weight or triglyceride (TG) or total cholesterol (TC) levels. The areas under the intraperitoneal glucose tolerance test (IPGTT) and the insulin tolerance test (ITT) curves were significantly decreased in HFD + vaspin group compared with the HFD group, and the glucose infusion rate (GIR) showed the same trends. Western blot, real-time polymerase chain reaction (RT-PCR) and immunofluorescence staining showed that vaspin could improve insulin resistance in liver, skeletal muscle and adipose tissue by activating the IRS/PI3K/Akt/Glut signalling pathway and inhibiting the IκBα/NF-κB signalling pathway.
Highlights
Insulin binds to and activates the tyrosine kinase activity of the insulin receptor on the cell surface, leading to the tyrosine phosphorylation and activation of insulin receptor substrate (IRS); activated IRS further activates protein kinase B (Akt) through the activation of phosphatidylinositol 3 kinase (PI3K) and promotes the membrane translocation of glucose transporters (Gluts), thereby reducing blood glucose levels[4,5,6,7]
Compared with rats in the normal control group (NC), those in the high-fat diet (HFD) group showed an increase in body weight, and the serum concentrations of fasting blood glucose (FBG), fasting insulin (FINS), triglyceride (TG) and total cholesterol (TC) were increased significantly (Fig. 1A–E)
Visceral adipose tissue-derived serpin (Vaspin) reversed the HFD-induced increases in serum TNF-α and interleukin 6 (IL-6) levels (Fig. 1F–G). These results suggest that vaspin improves Insulin resistance (IR), lowers blood glucose, and reduces inflammation
Summary
Insulin binds to and activates the tyrosine kinase activity of the insulin receptor on the cell surface, leading to the tyrosine phosphorylation and activation of insulin receptor substrate (IRS); activated IRS further activates protein kinase B (Akt) through the activation of phosphatidylinositol 3 kinase (PI3K) and promotes the membrane translocation of glucose transporters (Gluts), thereby reducing blood glucose levels[4,5,6,7]. Overexpression of inflammatory molecules downstream of NF-κB, www.nature.com/scientificreports/ Such as tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), can activate the NF-κB pathway, forming a vicious cycle in which the body remains in a chronic state of inflammation that further exacerbates IR13,19. In vascular smooth muscle cells, vaspin inhibits the activation of NF-κB/protein kinase C theta (PKCθ) by reactive oxygen species (ROS) and inhibits the expression of intercellular adhesion molecule-1 (ICAM-1) induced by TNF-α24. In this study, we used a high-fat diet (HFD) to establish an animal model of IR and performed hyperinsulinaemic-euglycaemic clamp, western blot, real-time polymerase chain reaction (RT-PCR) and immunofluorescence experiments to explore the ability of vaspin to improve IR through the IRS/ PI3K/Akt/Glut and IκBα/NF-κB signalling pathways
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