Estrogen-related receptor alpha inverse agonist enhances basal glucose uptake in myotubes through reactive oxygen species.
Estrogen-related receptors alpha (ERRalpha) and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) function coordinately to regulate mitochondrial biogenesis and oxidative phosphorylation particularly in muscle tissue. In this study, we addressed the consequences of suppressing the activity of ERRalpha in L6 myotubes using an ERRalpha inverse agonist XCT-790. We found that treating differentiated L6 myotubes with XCT-790 reduced the expression of PGC-1alpha and suppressed mitochondrial biogenesis. Additionally, XCT-790 increased the production of reactive oxygen species (ROS) which in turn induced the expressions of glucose transporters 1, 2, and 5 leading to an increase in glucose uptake and uncoupling protein 3 leading to a reduction of mitochondrial membrane potential. Thus, suppressing the activity of ERRalpha which is primarily responsible for controlling beta-oxidation would nonetheless indirectly affect glucose uptake in a ROS-dependent manner.
Chen
Lihua
L
Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou International Business Incubator.
Wong
Chiwai
C
D000818:Animals; D002460:Cell Line; D003847:Deoxyglucose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051246:Glucose Transport Proteins, Facilitative / Q000096:biosynthesis; D007473:Ion Channels / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000819:agonists* / Q000096:biosynthesis; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism; D000071247:Uncoupling Protein 3; D000097983:ERRalpha Estrogen-Related Receptor
D003847:Deoxyglucose; D005947:Glucose; D051246:Glucose Transport Proteins, Facilitative; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009570:Nitriles; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D013844:Thiazoles; D014157:Transcription Factors; D000071247:Uncoupling Protein 3; D000097983:ERRalpha Estrogen-Related Receptor; C501429:Ppargc1a protein, rat; C000604394:Ucp3 protein, rat; C488234:XCT790