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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0278v1 199/1/33    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Anedda, A. Articles by Gonzalez-Barroso, M. d. M. Search for Related Content PubMed PubMed Citation Articles by Anedda, A. Articles by Gonzalez-Barroso, M. d. M.

A Anedda, Molecular and Cellular Pathophysiology, Centro de Investigaciones Biologicas, CSIC, Madrid, Spain
E Rial, Molecular and Cellular Pathophysiology, Centro de Investigaciones Biologicas, CSIC, Madrid, Spain
M Gonzalez-Barroso, Molecular and Cellular Pathophysiology, Centro de Investigaciones Biologicas, CSIC, Madrid, Spain

Correspondence: Maria del Mar Gonzalez-Barroso, Email: margb{at}cib.csic.es

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 β-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 in the effects of metformin in white adipocytes. We studied the effect of this drug in differentiating 3T3-L1 adipocytes and we 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.

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