| Growing concern about the increasing prevalence of the metabolic syndrome and type 2 diabetes has generated substantial interest in the metabolic effects of antihypertensive drugs.AngiotensinⅡtype 1 receptor blocker(ARB)controls the blood pressure by blockade of the renin angiotensin system.The clinical studies reported a remarkably consistent reduction in the incidence of newly-onset type 2 diabetes in hypertensive patients treated with ARB and increase in insulin sensitivity.However,the precise mechanism of improving the insulin sensitivity remains to be determined.Objectives:To investigate the effects of AngiotensinⅡtype 1 receptor blocker -Candesartan on insulin sensitivity of high-fat diet induced obesity of rats and its possible molecular mechanisms.Methods:1.An obese rat model was induced by high fat feed and rats were orally administered with candesartan(8 mg/kg.d)for 4 weeks.Euglycemic hyperinsulinemic clamp technique were performed to estimate the insulin sensitivity among normal chow group(NC group),high fat diet group(HF group), and high-fat diet with daily candesartan treatment group(HF+C group).Blood samples were collected to test the blood glucose,lipid profile,insulin and other biochemical parameters.Viscera were taken out and weighed after rats were sacrificed from each group.2.The protein expressions of peroxisome proliferator activated receptor gamma(PPARγ)in liver and adipose tissue were respectively determined by immunohistochemistry and western blot.Activation of Glucose Transporter(GLUT4)in skeletal muscles were detected by immunohistochemical SP method,GLUT4 expressions were assayed by western blotting.3.The gene and protein expressions of JAK2 and PTP-1B in adipose tissue were confirmed by both RT-PCR and western blotting. Results:1.There were no significant difference in body weight among 8-week-old rats.The body weight,liver weight,heart weight,epididymal and peri-renal fat weight of HF group were significantly higher than those of NC group and HF+C group(all P＜0.01)when rats were 16 weeks old.Although TC and FINS of HF+C group were lower than those of HF group,ISI,AngⅡand Glucose infusion rate(GIR)of HF+C group were much higher than those of HF group.2.Further study revealed that expression of PPARγin liver and visceral adipose tissue.Under light microscope,positive staining was recognized by brown color.There were less stained nuclei of hepatocytes around portal and central vein areas and less stained peripheral nuclei of adipocytes in HF group than in HF+C group.The integral optical density(IOD)of PPARγin HF+C group were stronger than that in HF group.GLUT4 expression of rat skeletal muscle in HF+C group being identified by immunohistochemistry and western blot analysis were much higher than that in HF and NC group.3.The expressions of JAK mRNA and PTP-1B mRNA in adipose tissue in NC group were at relatively lower level,while in HF group the expressions markedly increased.The mRNA expressions of JAK2 and PTP-1B in HF+C group were significantly lower than those in HF group respectively(0.87±0.16 vs 1.51±0.09,0.91±0.13 vs 1.89±0.14,P＜0.05).The protein expressions of JAK2 and PTP-1B basically conformed with the gene expression:Although the expressions of JAK and PTP-1B in NC group were lower than those in HF group(0.57±0.09 vs 1.01±0.18,0.98±0.15 vs 1.57±0.24,P＜0.05),they were still higher than those in HF+C group(1.01±0.18 vs 0.57±0.09,1.57±0.24 vs 0.43±0.08,P＜0.05).The conclusions of this study were as follows:1.Obesity and hyperlipemia were induced in rats by high-fat diet for 8 weeks. Euglycemic-hyperinsulinemic clamp experiment testified decreased-GIR and hyperinsulinemia with normal FBG.The insulin resistant rat model was successfully duplicated with high fat feeding.2.Candesartan intervention could lower the body weight,epididymal and peri-renal fat weight,decrease the serum insulin and increase the GIR.Thus Candesartan might markedly improve insulin resistance in rats induced by high-fat diet.3.Hypertrophic fat cells displayed in rats of HF group.After candesartan treatment,enlarged adipocytes became smaller without changing the number of adipocytes due to the highly expression of PPARγ.Candesartan could promote the expression of PPARγin liver and adipose tissues.4.GLUT4 protein expressions in skeletal muscles in HF group were much lower than that in NC and HF+C group,which suggested that insulin resistance was associated with decreased GLUT4 expressions in peripheral tissues. Candesartan could partially reverse these effects and thus increase the sensitivity of body for the insulin.5.The gene and protein expressions of JAK2 and PTP-1B were higher in adipose tissue of rats of HF group.Candesartan could decrease their expression. The activation of AngⅡ→JAK2→Iκb/NF-κB→PKAc→PTP-1B pathway was the possible molecular mechanism leading to insulin resistance. |
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