Copper Metabolism And The Function Of CTR1 In The Mouse Adipose Tissue

Adipose tissue plays central roles in lipid metabolism,and is an important organ for energy storage and secreting of a lot of adipocytokines to regulate glucolipid metabolism.Adipose tissue is typically classed into three distinct subtypes,white adipose tissue(WAT),brown adipose tissue(BAT)or beige/brite adipose tissue.WAT storages lipid energy,while BAT contains a large number of mitochondrias,which express UCP1(uncoupling protein 1)specifically,consume lipid and release heat.Different from BAT,WAT appears BAT profile and gets the ability of thermogenesis by the cold induced browning.Copper(Cu)and iron(Fe)are the enzymatic cofactors required for many biochemical processes.Resent studies have linked Copper(Cu)and iron(Fe)to lipid metabolism.Copper regulates cAMP-dependent lipolysis.Ctrl is a high affinity copper transporter for the influx of copper into cell,while ATP7A and ATP7B are responseble for copper export.The mechanism of Ctrl,ATP7A and ATP7B regulated copper has been difinited,and there are many studies for the physiological effect of Ctrl conditional knockout in cells of tissues and organs,such as intestinal epithelial cells,hepatocyte and cardiomyocyte,the function of Ctrl and copper in adipose tissue and lipid metabolism is still unknown.However,most studies about Cu homeostasis and lipid metabolism focus on ATP7A and ATP7B,the transporter responsible for Cu export,and studies about Ctrl,the transporter responsible for Cu uptake,focus on the Cu homeostasis in cell and animal level,the role of Ctrl and Cu duing adipose tissue cell differiation remains unknown.To reveale the dynamic changes of Cu and Fe,we examined the level of Cu and Fe in interscapular brown adipose tissue(BAT)and subcutaneous white adipose tissue(subWAT)at different development stages.Our results suggested their potential roles in energy homeostasis.Furthermore,the Cu and Fe contents significantly increased and the expression of CTR1 and ATP7A upregulated in cold induced BAT,while the sub WAT has no these regularity changes,indicating Cu and Fe mainly involves in the activation of BAT.To further explore the role of Ctr1 in mice adipocyte differentiation and adipose tissue development,the mice model of Ctr1 conditional knockout in adipocytes were generated.The knockout mice(KO)had BAT hypertrophy and Cu level decreased,while the BAT of High FAT Diet KO was still hypertrophy.The cold exposure indicated defection of thermogenesis,resulted by the lack of Cu induced by Ctr1 knockout.In summary,the cold exposure of mice demonstrate that Cu and Fe involves the thermogenesis of BAT,and our data about KO mice further demonstrate the lack of Cu induced by Ctr1 knockout result in defection of BAT thermogenesis.