Etomoxir-induced increase in UCP3 supports a role of uncoupling protein 3 as a mitochondrial fatty acid anion exporter

P. Schrauwen*, V.B. Schrauwen-Hinderling, M.K.C. Hesselink, G. Schaart, C.F.P. Kornips, W.H.M. Saris, M.S. Westerterp-Plantenga, W. Langhans

*Corresponding author for this work

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Nutrition and Toxicology Research Institute Maastricht, Department of Human Biology, Maastricht University, 6200 MD Maastricht, The Netherlands.

The physiological function of human uncoupling protein-3 is still unknown. Uncoupling protein-3 is increased during fasting and high-fat feeding. In these situations the availability of fatty acids to the mitochondria exceeds the capacity to metabolize fatty acids, suggesting a role for uncoupling protein-3 in handling of non-metabolizable fatty acids. To test the hypothesis that uncoupling protein-3 acts as a mitochondrial exporter of non-metabolizable fatty acids from the mitochondrial matrix, we gave human subjects Etomoxir (which blocks mitochondrial entry of fatty acids) or placebo in a cross-over design during a 36-h stay in a respiration chamber. Etomoxir inhibited 24-h fat oxidation and fat oxidation during exercise by approximately 14-19%. Surprisingly, uncoupling protein-3 content in human vastus lateralis muscle was markedly up-regulated within 36 h of Etomoxir administration. Up-regulation of uncoupling protein-3 was accompanied by lowered fasting blood glucose and increased translocation of glucose transporter-4. These data support the hypothesis that the physiological function of uncoupling protein-3 is to facilitate the outward transport of non-metabolizable fatty acids from the mitochondrial matrix and thus prevents mitochondria from the potential deleterious effects of high fatty acid levels. In addition our data show that up-regulation of uncoupling protein-3 can be beneficial in the treatment of type 2 diabetes.

Publication Types:
Clinical Trial
Controlled Clinical Trial
Original languageEnglish
Pages (from-to)1688-1690
Number of pages3
JournalFaseb Journal
Issue number12
Publication statusPublished - 1 Jan 2002


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