الفهرس 
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Abstract
Obesity is a dominant risk factor for the development of Mets, which represents a constellation of derangements, including insulin resistance, atherogenic dyslipidemia, hyperglycemia and hypertension, representing a risk factor for cardiovascular disease (CVD) and type 2 diabetes (T2D). The modern lifestyle of high-fat diet (HFD) and lack of physical activity is one of the most important risk factors that cause an increase in adipose tissue and hence increase the incidence of obesity. The study aimed to establish a model of Mets in rats and to evaluate the potential protective influence of tiron and protocatechuic acid (PCA) against high fat diet (HFD)-induced Mets sequelae. In the present study, HFD was used to induce Mets. Sprague–Dawley (SD) rats were fed 60 % HFD for 14 weeks and tiron (100, 200 mg/kg/day, IP), PCA (50, 100 mg/kg/day, orally) and MET (100 mg/kg, orally) were started on day 1 and continued till the end of experiment. At the end of the experiment, blood samples were collected and serum was used for biochemical measurements (lipid profile, liver enzymes, pro-inflammatory markers). In addition, biological samples were collected, including liver tissues, adipose tissues, soleus muscles as well as aortas for determination of oxidative stress markers, flow cytometry analysis, histopathological and immunohistochemical examination. HFD-fed rats exhibited significant decrease in food intake; yet, body weight, feeding efficiency ratio and anthropometrical parameters were increased. Moreover, insulin sensitivity was impaired as indicated by significant elevations in glucose AUC during oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) and homeostasis model assessment of insulin resistance (HOMA-IR) index. Furthermore, chronic HFD feeding elicited significant elevations in serum lipid profile consistent with increase in free fatty acids (FFAs) level and liver enzymes (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) activity with concomitant hepatic steatosis. Additionally, serum C-reactive protein (CRP), monocyte chemoattractnt protein 1(MCP-1), interleukin 1b (Il-1b) levels and tissue malondialdehyde (MDA) activity were increased while superoxide dismutase (SOD), glutathione (GSH) activity and adiponectin (ADP) level were decreased. Moreover, insulin signaling pathway was markedly impaired in soleus muscles, as indicated by a decrease in insulin‐induced AKT phosphorylation. Furthermore, HFD prompted endothelial dysfunction as confirmed by significant reduction in aortic eNOS expression via immunohistochemical examination. Histopathologically, adipose tissues showed increases in adipocyte size and flow cytometry analysis of adipose tissue from HFD-fed rats confirmed a significant increase in the percentage of number of CD68+ cells. Tiron and PCA administration succeeded to attenuate HFD-induced obesity via improvement of anthropometrical parameters as well as increase of ADP level. Additionally, insulin resistance was attenuated upon administration of both Tiron and PCA, as indicated by reduction of fasting blood glucose, fasting insulin, AUCOGTT, AUCITT and HOMA-IR index. Moreover, both drugs attenuated HFD-induced dyslipidemia via improvement of lipid profile (reduced TC, TGs, LDL-C and VLDL-C) with a reduction in FFAs and mitigation of liver steatosis. Furthermore, both drugs diminished oxidative stress in soleus muscle and hepatic tissues (decreased MDA activity while increased SOD and GSH activity) and pro-inflammatory markers in serum (decreased CRP, MCP-1 and Il-1b levels). In addition, tiron and PCA enhanced insulin signaling in soleus muscles via increase in AKT phosphorylation. Moreover, both of tiron and PCA attenuated HFD-induced decrease in aortic eNOS expression as confirmed by marked increase in aortic eNOS expression. Histopathologically, adipose tissues showed decreases in adipocyte size upon administration of tiron and PCA. Also, flow cytometry analysis of adipose tissue from HFD-fed rats confirmed a significant reduction in the percentage of number of CD68+ cells upon administration of both drugs. In conclusion : This study showed that administration of both PCA and tiron could protect against HFD-induced Mets, possibly via their hypoglycemic, insulin-sensitizing, anti-oxidant, anti-inflammatory, hypolipidemic and hepatoprotective effects. However, more investigations are required to elucidate their precise mechanism of action.