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IMD Improved HFD-induced Insulin Resistance through Inhibition of Chronic Inflammation in Adipose tissue

【摘要】:正Objective Adipose tissue plays a vital role in regulating the whole body glucose homeostasis. Chronic inflammation in adipose tissue,regulated by many endocrine factors,is one of the main pathogenesis of insulin resistance and type 2 diabetes.Calcitonin gene - related peptide(CGRP) family,such as CGRP and adrenomedullin(ADM),take part in ameliorating inflammation.Intermedin(IMD),a 53 amino acids peptide and a novel member of the CGRP family,is an endogenous cardiovascular - protective peptide.The aim of this study is to determine whether intermedin could improve high fat diet(HFD) - induced insulin resistance by depressed chronic inflammation in adipose tissue.Material and Methods C57 mice(16 weeks old) were fed with chow or HFD for 8 weeks.From the fifth week,osmotic pumps filled with IMD(300 ng/ kg/h) or saline were planted subcutaneously.After 8 weeks of HFD,glucose tolerance test(GTT),insulin tolerance test(ITT),and Euglycemic - hyperinsulinemic clamp(EHC) test were performed,and then mice were sacrificed to measure inflamatory cytokines,insulin,free fatty acid and epididymal fat weight.For in vitro study,primary rat adipocytes and fully differentiated 3T3 - L1 adipocytes were used.Results HFD significantly impaired insulin sensitivity in C57 mice assessed by GTT,ITT,and EHC.The expression of IMD and receptor activity - modifying proteins(RAMP1,RAMP2,RAMP3 ) in adipose tissue were significantly decreased in these mice or db/db mice.When the mice were administered with IMD for 4 weeks,the decreases of RAMPs were rescued in HFD mice,and these mice showed lower fasting blood glucose and insulin levels than saline control group.IMD improved HFD - induced insulin resistance confirmed by GTT,ITT and EHC test without alterating mouse food intake.Furthermore,MD treatment increased insulin - induced phsphorilation of AKT in adipose tissue,liver and skeletal muscle in HFD mice.HFD mice showed increased levels of plasma inflammatory cytokines(TNFα,IL - 6,MCP - 1) and plasma free fatty acid than chow diet fed mice,while IMD treatment significantly lowered these increases.In addition,histological analysis of HE - and immuno - stain showed much smaller lipid droplet,less crown like structures,and much less inflammatory cell infiltration in adipose tissue from IMD group.And IMD treatment also significantly decreased HFD -enhanced inflammatory cytokine levels(TNFα,IL - 6 and MCP - 1) in adipose tissue assessed by immunostain and real - time PCR.To explore the potential mechanisms by which IMD improved HFD - induced insulin resistance and inflammation of adipose tissue,we cultured primary rat adipocytes and 3T3 - L1 cells pretreated with IMD.The results showed that IMD pretreatment attenuated TNFα- induced inflammatory cytokines' mRNA expression and secretion.And TNFαinduced IKK phosphorilation,IκBαdegradation,p65 nuclear - translocation and NF -κB activity were all reduced by IMD.Meanwhile,IMD increased AMPK and ACC phosphorilation in a time and dose - dependent manner in adipocytes.When AMPK activation was blocked by compound C,the inhibitive effects of IMD on TNFα- stimulated NF -κB activation were impaired. Conclusions These results indicate that IMD treatment improves insulin resistance in HFD mice, and the underlying mechanisms may involve suppressing chronic inflammation through AMPK - dependent inhibition of NF -κB signalling in adipose tissue.

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