脂肪因子chemerin在饮食和运动调控小鼠骨骼肌脂质沉积中的作用

Effects of chemerin on diet-and exercise-regulated lipid deposition in skeletal muscles of mice

目的:探讨维甲酸受体应答基因2(retinoic acid receptor responder 2,Rarres2)编码的脂肪因子chemerin在饮食和运动调控小鼠骨骼肌脂质沉积中的作用。方法:将8周龄野生型(wild-type,WT)小鼠、脂肪特异性Rarres2基因敲除(adipose-specific Rarres2 gene knockout,adipo-Rarres2^(−/−))小鼠和全身性Rarres2基因敲除(global Rarres2 gene knockout,Rarres2^(−/−))小鼠随机分为普通饮食(normal diet,ND)组和高脂饮食(high-fat diet,HFD)组,即ND+WT组、ND+adipo-Rarres2^(−/−)组、ND+Rarres2^(−/−)组、HFD+WT组、HFD+adipo-Rarres2^(−/−)组和HFD+Rarres2^(−/−)组,共6组,每组6只。此外,让HFD组的3种小鼠完成6周的中等强度跑台运动,即WT+运动(exercise,Exe)组、adipo-Rarres2^(−/−)+Exe组和Rarres2^(−/−)+Exe组,每组6只。油红O染色及骨骼肌内甘油三酯(triglyceride,TG)和游离脂肪酸(free fatty acid,FFA)定量检测小鼠骨骼肌脂质沉积;胰岛素耐量实验和葡萄糖耐量实验检测胰岛素敏感性;Western blot检测骨骼肌脂肪酸转位酶(fatty acid translocase,FAT/CD36)、肉碱棕榈酰基转移酶1(carnitine palmitoyltransferase 1,CPT1)、过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptorα,PPARα)、硬脂酰辅酶A去饱和酶1(stearoyl-coenzyme A desaturase 1,SCD1)和葡萄糖转运蛋白4(glucose transporter 4,GLUT4)的蛋白水平。结果:(1)ND+Rarres2^(−/−)组和HFD+Rarres2^(−/−)组小鼠骨骼肌脂质沉积均加重(P<0.01),胰岛素敏感性均下降(P<0.05);但HFD+adipo-Rarres2^(−/−)组小鼠骨骼肌脂质沉积却显著减轻(P<0.01)。(2)ND+Rarres2^(−/−)组和HFD+Rarres2^(−/−)组小鼠骨骼肌CPT1和GLUT4蛋白水平均下调(P<0.05),SCD1水平上调(仅HFD+Rarres2^(−/−)组,P<0.01);但HFD+adipo-Rarres2^(−/−)组小鼠骨骼肌CPT1和GLUT4蛋白水平上调(P<0.01),CD36蛋白水平下调(P<0.01)。(3)HFD下,与WT+Exe组相比,adipo-Rarres2^(−/−)+Exe组和Rarres2^(−/−)+Exe组小鼠中运动对骨骼肌脂质沉积的抑制作用减弱,以Rarres2^(−/−)+Exe组减弱得更显著。结论:编码chemerin的Rarres2基因敲除不仅影响HFD小鼠骨骼肌脂质沉积,而且还减弱运动对HFD小鼠骨骼肌脂质沉积的抑制作用;该作用与Rarres2基因敲除改变骨骼肌糖脂代谢相关蛋白水平有关。

AIM:To explore the role of chemerin,encoded by retinoic acid receptor responder 2(Rarres2)gene,in the regulation of skeletal muscle lipid deposition by diet and exercise interventions in mice.METHODS:Eightweek-old wild-type(WT)mice,adipose-specific Rarres2 gene knockout(adipo-Rarres2^(−/−))mice and global Rarres2 gene knockout(Rarres2^(−/−))mice were randomly divided into normal diet(ND)and high-fat diet(HFD)groups,namely ND+WT group,ND+adipo-Rarres2^(−/−)group,ND+Rarres2^(−/−)group,HFD+WT group,HFD+adipo-Rarres2^(−/−)group,and HFD+Rarres2^(−/−)group,with 6 mice in each group.The mice in HFD groups were divided into 3 groups with 6-week moderate-intensity running(n=6),namely WT+exercise(Exe)group,adipo-Rarres2^(−/−)+Exe group,and Rarres2^(−/−)+Exe group.Skeletal muscle lipid deposition was analyzed by oil red O staining and quantified by triglyceride(TG)and free fatty acid(FFA)detection.Insulin tolerance and oral glucose tolerance tests were performed to evaluate insulin sensitivity.The protein levels of fatty acid translocase(FAT/CD36),carnitine palmitoyltransferase 1(CPT1),peroxisome proliferator-activated receptorα(PPARα),stearoyl-coenzyme A desaturase 1(SCD1)and glucose transporter protein 4(GLUT4)in skeletal muscles were detected by Western blot.RESULTS:(1)In both ND+Rarres2^(−/−)and HFD+Rarres2^(−/−)groups,skeletal muscle lipid deposition was aggravated(P<0.01)and the insulin sensitivity decreased(P<0.05).By contrast,skeletal muscle lipid deposition was significantly attenuated in HFD+adipo-Rarres2^(−/−)group(P<0.01).(2)The protein levels of CPT1 and GLUT4 in skeletal muscles decreased in ND+Rarres2^(−/−)and HFD+Rarres2^(−/−)groups(P<0.05),and the SCD1 level increased in HFD+Rarres2^(−/−)group(P<0.01).The protein levels of CPT1 and GLUT4 in skeletal muscles increased,and the CD36 protein level decreased in HFD+adipo-Rarres2^(−/−)group(P<0.01).(3)The inhibitory effect of exercise on skeletal muscle lipid deposition was weakened in adipo-Rarres2^(−/−)+Exe and Rarres2^(−/−)+Exe groups compared with WT+Exe group,and the effect was more significantly weakened in Rarres2^(−/−)+Exe group.CONCLUSION:Knockout of chemerin-encoding Rarres2 gene not only influences skeletal muscle lipid deposition in HFD mice,but also reduces exercise-induced attenuation of lipid deposition in the skeletal muscle of HFD mice.These effects are associated with the changes in glucose and lipid metabolism-related proteins.