Submitted on November 19, 2004
Revised on February 15, 2005
Accepted on February 23, 2005
Reduced fatty acid 
-oxidation and increased glucose uptake mediate lipid accumulation in 3T3-L1 in response to mitochondrial dysfunction
Sébastien Vankoningsloo, Marie Piens, Christophe Lecocq, Audrey Gilson, Aurélia De Pauw, Patricia Renard, Catherine Demazy, Andrée Houbion, Martine Raes, and Thierry Arnould
Department of Biology, University of Namur (F.U.N.D.P.), Namur 5000
Corresponding Author: thierry.arnould{at}fundp.ac.be
Mitochondrial cytopathy has been associated with modifications of lipid metabolism in various situations such as the acquisition of an abnormal adipocyte phenotype observed in multiple symmetrical lipomatosis or the triglyceride accumulation in muscles associated with the MERRF syndrome. However, the molecular signaling leading to fat metabolism dysregulation in cells with impaired mitochondrial activity is still poorly understood. Here, we found that preadipocytes incubated with inhibitors of mitochondrial respiration such as antimycin A accumulate triglyceride vesicles but do not acquire specific markers of adipocytes. While the uptake of triglyceride precursors is not stimulated in 3T3-L1 cells with impaired mitochondrial activity, we found a strong stimulation of glucose uptake in antimycin A-treated cells mediated by calcium and PI 3-kinase/Akt1/GSK3
, a pathway known to trigger the translocation of GLUT4 to the plasma membrane in response to insulin. Triglyceride accumulation in antimycin A-treated cells is mediated by a reduced PPAR
activity that down-regulates muscle-CPT-1 expression and fatty acid -oxidation, and by a direct conversion of glucose into triglycerides accompanied by the activation of ChREBP, a lipogenic transcription factor. Taken together, these results could explain how mitochondrial impairment leads to the multivesicular phenotype found in some mitochondria-originating diseases associated with a dysfunction in fat metabolism.
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