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Am J Physiol Endocrinol Metab 295: E678-E685, 2008. First published July 1, 2008; doi:10.1152/ajpendo.90287.2008
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Deleterious action of FA metabolites on ATP synthesis: possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance

Muhammad A. Abdul-Ghani,1 Florian L. Muller,2 Yuhong Liu,2 Alberto O. Chavez,1 Bogdan Balas,1 Pengou Zuo,1 Zhi Chang,1 Devjit Tripathy,1 Rucha Jani,1 Marjorie Molina-Carrion, Adriana Monroy,1 Franco Folli,1 Holly Van Remmen,2 and Ralph A. DeFronzo1

1Division of Diabetes, 2Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas

Submitted 12 March 2008 ; accepted in final form 25 June 2008

Insulin resistance is a characteristic feature of type 2 diabetes and obesity. Insulin-resistant individuals manifest multiple disturbances in free fatty acid (FFA) metabolism and have excessive lipid accumulation in insulin target tissues. Although much evidence supports a causal role for altered FFA metabolism in the development of insulin resistance, i.e., "lipotoxicity", the intracellular mechanisms by which elevated plasma FFA levels cause insulin resistance have yet to be completely elucidated. Recent studies have implicated a possible role for mitochondrial dysfunction in the pathogenesis of insulin resistance in skeletal muscle. We examined the effect of FFA metabolites [palmitoyl carnitine (PC), palmitoyl-coenzyme A (CoA), and oleoyl-CoA] on ATP synthesis in mitochondria isolated from mouse and human skeletal muscle. At concentrations ranging from 0.5 to 2 µM, these FFA metabolites stimulated ATP synthesis; however, above 5 µM, there was a dose-response inhibition of ATP synthesis. Furthermore, 10 µM PC inhibits ATP synthesis from pyruvate. Elevated PC concentrations (≥10 µM) inhibit electron transport chain activity and decrease the mitochondrial inner membrane potential. These acquired mitochondrial defects, caused by a physiological increase in the concentration of FFA metabolites, provide a mechanistic link between lipotoxicity, mitochondrial dysfunction, and muscle insulin resistance.

palmitoyl carnitine; palmitoyl-coenzyme A; oleoyl-coenzyme A; mitochondria; adenosine 5'-triphosphate synthesis; insulin resistance; type 2 diabetes


Address for reprint requests and other correspondence: M. A. Abdul-Ghani, Division of Diabetes, Univ. of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229 (e-mail: abdulghani{at}uthscsa.edu)






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