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Fat and insulin resistance Sharing Relationship

Author: BaiXiuPing
Tutor: YangWenYing；LiHongLiang；XiaoJianZhong
School: Peking Union Medical College , China
Course: Endocrinology
Keywords: Insulin resistance Genes related to lipid metabolism Fenofibrate SD rat Fat partitioning Insulin resistance High-fat diet Genes related to lipid metabolism Genes related to insulin signaling liver muscle intralipid
CLC: R587.1
Type: PhD thesis
Year: 2008
Downloads: 443
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Abstract

PARTⅠ:The mechanism and relationship between genes expression related to lipid metabolism and insulin resistanceOBJECTIVE-To observe the mechanism and relationship between changes of expression of genes related to lipid metabolism and insulin resistance induced by high fat diet in SD rats.RESEARCH DESIGN AND METHODS-Normal 8 weeks old male SD rats were randomly divided into three groups.They were fed with normal chow（NC,n= 10）,high fat diet（HF,n=10） and high fat diet supplemented with fenofibrate（FF,n=12）. Fenofibrate was given orally by 50mg·kg^-1·d^-1.The TG content of liver and skeletal muscle was measured.Glucose infusion rate（GIR） was used to evaluate the insulin sensitivity by using euglycemic-hyperinsulinemic clamp method.Genes expression was investigated using real-time PCR method.RESULTS-As compared with NC group,after high fat-feeding for 20 weeks,serum TG,the content of TG in liver and skeletal muscle in HF group increased 0.45-fold,2.14-fold and 10.64-fold,respectively.The change of TG content in liver and skeletal muscle was associated with the reduction of GIR[（6.16±0.75）mg·kg^-1·min^-1 vs （15.82±2.10）mg·kg^-1·min^-1（P＜0.01）].And Compared with NC group,the expression of hormone-sensitive lipase（HSL） and fatty-acid synthase（FAS） gene was enhanced by 28.2%and 21.3%respectively（P＜0.05）;the expression of acetyl-COA carboxylasel（ACC1） mRNA in liver increased 48.3%（P＜0.05）;the expression of acetyl-COA carboxylase（ACC2） was increased 101%（P＜0.01） and carnitine palmitoyltransferase 1（CPT-1） was reduced 71%（P＜0.01） in skeletal musclen in HF group.As compared with HF group,GIR increased 2.52 fold in FF group,in contrast, serum TG,liver TG and muscle TG were decreased about 70%,81%and 82%respectively in the fenofibrate treated group（P＜0.05）.Accordingly,the expression of FAS and HSL in adipose tissue and the expression of ACC1 in liver were decreased（P＜0.05）;in addition, the expression of CPT-1 was enhanced and ACC2 was decreased in muscle（P＜0.01） in FF group.CONCLUSIONS-The changing expression of genes which related to lipid metabolism may be have a role in accumulation of lipid in non-adipose tissues and insulin resistance in rats induced by high fat diet. PARTⅡ:The sequence of fat partitioning and its relationship with insulin resistanceOBJECTIVE-To observe the sequence of fat partitioning and its relationship with whole body insulin resistance（IR） in SD rats induced by a high-fat diet.RESEARCH DESIGN AND METHODS-SD rats were fed a normal or high-fat diet for 20 weeks.Serum triglycerides（TG）,serum free fatty acids（FFA）,fasting plasma glucose（FPG）,and liver and skeletal muscle TG were measured.The glucose infusion rate（GIR） and mRNA levels of acetyl-CoA carboxylase（ACC） and camitine palmitoyltransferase 1（CPT-1） in the liver and skeletal muscle were determined at different stages.RESULTS-Compared with rats fed the normal diet,serum FFA was not significantly increased in rats fed the high-fat diet until 20 weeks.In contrast,liver TG was significantly increased by the high-fat diet at 4 weeks（20-fold;P＜0.01）,and this continued until the end of the study.However,skeletal muscle TG was not significantly increased by the high-fat diet until 20 weeks（10.6-fold;P＜0.01）,and neither was the FPG.The GIR was significantly reduced（1.6-fold;P＜0.01） by the high-fat diet after 8 weeks.The mRNA levels of ACC and CPT-1 gradually increased and decreased over time,respectively,in both the liver and skeletal muscle in rats fed the high-fat diet.CONCLUSIONS-Lipid accumulation in the liver occurs earlier than lipid accumulation in the skeletal muscle.Fatty liver may be one of the early markers of whole body IR.Changes in the gene expression levels of ACC and CPT-1 may have important roles in the process of IR development. PARTⅢ:The effect of elevation of FFA on the expression of genes involved in lipid metabolism and insulin signaling transduction in liver and skeletal muscle in SD ratsOBJECTIVE-To observe the effect of elevation of FFA on the expression of genes involved in lipid metabolism and insulin signaling transduction in liver and skeletal muscle in SD rats.RESEARCH DESIGN AND METHODS-Normal 8 weeks old male SD rats were randomly divided into two groups.Normal control group was infused with normal saline （NC,n=10） and another group was infused with intralipid emulsion plus heparin（IC, n=10） respectively.Serum TG,FFA,liver TG and muscle TG were measured;Glucose infusion rate（GIR） and the level of mRNA of genes related to lipid metabolism and insulin signaling transduction in liver and muscle were determined.GIR was detected by using euglycemic-hyperinsulinemic clamp method,and GIR being used to evaluate the insulin sensitivity.Gene expression was investigated using Real-time PCR method.RESULTS-As compared with the NC group,after intralipid infusion for 6 hour,serum TG,FFA,the content of TG in liver was increased obviously,and TG of skeletal muscle in the IC group was not increased significantly.After intralipid infusion,GIR in the IC group decreased obviously.And in the normal control group,the expression of genes involved in lipogenesis such as SREBP-1,ACC1,DGAT1,DGAT2,GPAT is higher than skeletal muscle,after intralipid infusion they all decreased,the expression of genes involved in lipid oxidation such as UCP2,UCP3 is higher in skeletal muscle,after intralipid infusion they all increased,and the expression of fatty acid transporter CD36 is higher in skeletal muscle,after intralipid infusion it decreased.On the other hand,in the normal control group,the expression of genes involved in insulin signaling such as IR,IRSI,IRS2 is higher in skeletal muscle than liver,after intralipid infusion they all decreased. CONCLUSIONS-The expression of genes involved in lipogenesis in liver is higher than skeletal muscle,and the expression of genes involved in lipid oxidation in skeletal muscle is higher than liver,after intralipid infusion,they all changed.The different expression of genes involeved in lipid metabolism may have a role in different distribution of fat in liver and skeletal muscle.And the expression of genes involved in insulin signaling in skeletal muscle is higher than liver,after intralipid infusion they all decreased.The elevation of plasma FFA may impaired insulin signaling transduction directly.

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