title: Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels.
abstract: Metformin is a drug widely used to treat type 2 diabetes. It enhances insulin sensitivity by improving glucose utilization in tissues like liver or muscle. Metformin inhibits respiration, and the decrease in cellular energy activates the AMP-activated protein kinase that in turn switches on catabolic pathways. Moreover, metformin increases lipolysis and beta-oxidation in white adipose tissue, thereby reducing the triglyceride stores. The uncoupling proteins (UCPs) are transporters that lower the efficiency of mitochondrial oxidative phosphorylation. UCP2 is thought to protect against oxidative stress although, alternatively, it could play an energy dissipation role. The aim of this work was to analyse the involvement of UCP2 on the effects of metformin in white adipocytes. We studied the effect of this drug in differentiating 3T3-L1 adipocytes and found that metformin causes oxidative stress since it increases the levels of reactive oxygen species (ROS) and lowers the aconitase activity. Variations in UCP2 protein levels parallel those of ROS. Metformin also increases lipolysis in these cells although only when the levels of ROS and UCP2 have decreased. Hence, UCP2 does not appear to be needed to facilitate fatty acid oxidation. Furthermore, treatment of C57BL/6 mice with metformin also augmented the levels of UCP2 in epididymal white adipose tissue. We conclude that metformin treatment leads to the overexpression of UCP2 in adipocytes to minimize the oxidative stress that is probably due to the inhibition of respiration caused by the drug.
authors.affiliation: Department of Cellular and Molecular Physiopathology, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Anedda
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rial
authors.forename: M Mar
authors.initials: MM
authors.lastname: González-Barroso
mesh_terms: D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008066:Lipolysis / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D000071246:Uncoupling Protein 2
chemical_list: D007004:Hypoglycemic Agents; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D008687:Metformin